Search

Hypoxia (low-oxygen) is one of the most common characteristics of solid tumours. Exploiting tumour hypoxia to reductively activate Pt(IV) prodrugs has the potential to deliver toxic Pt(II) selectively and thus overcome the systemic toxicity issues of traditional Pt(II) therapies. However, our current understanding of the behaviour of Pt(IV) prodrugs in hypoxia is limited. Here, we evaluated and compared the aryl carbamate fluorogenic Pt(IV) complexes, CisNap and CarboNap, as well as the previously reported OxaliNap, as potential hypoxia-activated Pt(IV) (HAPt) prodrugs. Low intracellular oxygen concentrations (<0.1%) induced the greatest changes in the respective fluorescence emission channels. However, no correlation between reduction under hypoxic conditions and toxicity was observed, except in the case for CarboNap, which displayed significant hypoxia-dependent toxicity. Other aryl carbamate Pt(IV) derivatives (including non-fluorescent analogues) mirrored these observations, where carboplatin(IV) derivative CarboPhen displayed a hypoxia-selective cytotoxicity similar to that of CarboNap. These findings underscore the need to perform extensive structure activity relationship studies on the cytotoxicity of Pt(IV) complexes under normoxic and hypoxic conditions.

Though platinum (Pt)-based complexes have been recently exploited as immunogenic cell death (ICD) inducers for activating immunotherapy, the effective activation of sufficient immune responses with minimal side effects in deep-seated tumors remains a formidable challenge. Herein, we propose the first example of a near-infrared (NIR) light-activated and lysosomal targeted Pt(II) metallacycle (1) as a supramolecular ICD inducer. 1 synergistically potentiates immunomodulatory response in deep-seated tumors via multiple-regulated approaches, involving NIR light excitation, boosted reactive oxygen species (ROS) generation, good selectivity between normal and tumor cells, and enhanced tumor penetration/retention capabilities. Specifically, 1 has excellent depth-activated ROS production (~7 mm), accompanied by strong anti-diffusion and anti-ROS quenching ability. In vitro experiments demonstrate that 1 exhibits significant cellular uptake and ROS generation in tumor cells as well as respective multicellular tumor spheroids. Based on these advantages, 1 induces a more efficient ICD in an ultralow dose (i.e., 5 μM) compared with the clinical ICD inducer-oxaliplatin (300 μM). In vivo, vaccination experiments further demonstrate that 1 serves as a potent ICD inducer through eliciting CD8 + /CD4 + T cell response and Foxp3 + T cell depletion with negligible adverse effects. This study pioneers a promising avenue for safe and effective metal-based ICD agents in immunotherapy., (© 2024 Wiley-VCH GmbH.)

The search for better chemotherapeutic drugs to alleviate the deficiencies of existing platinum (Pt) drugs has picked up the pace in the millennium. There has been a disparate effort to design better and safer Pt drugs to deal with the problems of deactivation, Pt resistance and toxic side effects of clinical Pt drugs. In this review, we have discussed the potential of kinetically inert Pt complexes as an emerging class of next-generation Pt drugs. The introduction gives an overview about the development, use, mechanism of action and side effects of clinical Pt drugs as well as the various approaches to improve some of their pharmacological properties. We then describe the impact of kinetic lability on the pharmacology of functional Pt drugs including deactivation, antitumor efficacy, toxicity and resistance. Following a brief overview of numerous pharmacological advantages that a non-functional kinetically inert Pt complex can offer; we discussed structurally different classes of kinetically inert Pt (II) complexes highlighting their unique pharmacological features., (© 2024 Wiley-VCH GmbH.)

Introduction: The purpose of this research was to determine how the P53/microRNA-34a (miR-34a)/survivin pathway contributes to oxaliplatin-induced (L-OHP) cell inhibition in gastric cancer., Methods: The BGC-823 gastric cancer cells were selected, and we examined their viability following treatment with L-OHP at different concentrations and time periods. The expression levels of miR-34a, P53, and survivin in the cells were determined., Results: In the 12- and 24-h groups, drug concentration of 15 μg/cm² (p < .005 in both) significantly lowered cell viability. In comparison to the control group, miR-34a mRNA expression, P53 mRNA expression, and protein expression were all significantly greater in the 24-h group (p = .0324, p = .0069, p = .0260, respectively), but survivin mRNA and protein expressions were significantly lower than those in the control group (p = .0338, p = .0032, respectively). There was a significant decrease in gastric cancer cells in the miR-34a overexpression group (p = .0020), a significant increase in P53 mRNA and protein expression compared to the control group (p = .0080, p = .0121, respectively), and a significant decrease in survivin mRNA and protein expression compared to the control group. (p = .0213, p = .0069, respectively)., Conclusion: Oxaliplatin inhibits tumor growth, invasion, and metastasis by upregulating miR-34a, activating the expression of the upstream P53 gene, and driving the downregulation of survivin (P53/miR-34a/survivin axis) in BGC-823 gastric cancer cells., (© 2024 The Author(s). Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

The activation of tumor cell immunogenicity through oxaliplatin (OXP)-induced immunogenic cell death (ICD) has significant implications in cancer treatment. However, the anti-tumor effect of OXP monotherapy still has many shortcomings, and the systemic administration of OXP leads to low drug concentration at the tumor site, which is susceptible to systemic toxic side effects. In this study, a combined therapeutic strategy using folate-modified nanoliposomes co-delivered with rapamycin (Rapa) and OXP (abbreviated as FA@R/O Lps) is proposed for the treatment of colorectal cancer (CRC). Rapa and OXP can directly inhibit tumor cell proliferation and induce apoptosis. OXP induces ICD by triggering the release of danger signals, such as HMGB1, ATP, and calreticulin. FA@R/O Lps with a particle size of about 134.1±1.8 nm and a small dispersion were successfully prepared. This novel liposomal system can be used to target and increase drug accumulation in tumors. In-vivo experiments showed that FA@R/O Lps successfully inhibit CRC growth and liver metastasis, and simultaneously reduce off-target toxicity. In particular, FA@R/O Lps showed greater therapeutic effects than free Rapa/OXP and R/O Lps. Taken together, this study provides a novel combination of Rapa and OXP, and a nano-delivery system for enhanced anti-CRC efficacy. The results suggest that FA@R/O Lps could be a promising strategy for the treatment of CRC., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pengke Yan reports financial support was provided by he Natural Science Foundation of Guangdong Province (No. 2022A1515010199). Wengting Zhu reports financial support was provided by Plan on Enhancing Scientific Research in GMU (2024SRP104). Wengting Zhu reports financial support was provided by Lin He’s New Medicine and Clinical Translation Academician Workstation Research Fund (2021HLKY07). Hanhui Huang reports financial support was provided by Medical Scientific Research Foundation of Guangdong Province(B2023154). Pengke Yan, and Wengting Zhureport financial support was provided by Guangzhou Basic and Applied Basic Research Foundation (2024A03J0189, 2024A03J0188). Hang Yu reports financial support was provided by Medical Scientific Research Foundation of Guangdong Province (A2024212). Pengke Yan reports financial support was provided by Guangzhou Municipal Bureau of Science and Technology Key Research and Development Program (2024B03J0056). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Platinum(II)-based drugs (Pt II ), which hinder DNA replication, are the most widely used chemotherapeutics. However, current Pt II drugs often miss their DNA targets, leading to severe side effects and drug resistance. To overcome this challenge, we developed a oxaliplatin-based platinum(IV) (Pt IV ) prodrug amphiphile (C 16 -OPt IV -R 8 K), integrating a long-chain hydrophobic lipid and a nucleus-targeting hydrophilic peptide (R 8 K). This design allows the prodrug to self-assemble into highly uniform lipid nanoparticles (NTPt IV ) for enhanced targeting chemotherapy and immunotherapy. Subsequently, NTPt IV 's bioactivity and effects were examined at diverse levels, encompassing cancer cells, 3D tumor spheres, and in vivo. Our in vitro studies show a 74% cancer cell nucleus localization of platinum drugs-3.6 times higher than that of oxaliplatin, achieving more than a ten-fold increase in eliminating drug-resistant cancer cells. In vivo, NTPt IV shows efficient tumor accumulation, leading to suppressed tumor growth of murine breast cancer. Moreover, NTPt IV recruited more CD4 + and CD8 + T cells and reduced CD4 + Foxp3 + Tregs to synergistically enhance targeted chemotherapy and immunotherapy. Overall, this strategy presents a promising advancement in nucleus-targeted cancer therapy, synergistically boosting the efficacy of chemotherapy and immunotherapy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lobaplatin shows antitumor activity against a wide range of tumors, including triple-negative breast cancer (TNBC), and has been linked to cancer stem cell pool. Here, we investigated the molecular mechanisms behind lobaplatin resistance and stemness in vitro and in vivo. Two chemoresistance-related GEO data sets (GSE70690 and GSE103115) were included to screen out relevant genes. Cysteine-rich secretory protein 3 (CRISP3) was found to be overexpressed in lobaplatin-resistant TNBC and related to poor diagnosis. CRISP3 expression was significantly correlated with tumor stemness markers in lobaplatin-resistant cells. E1A-associated protein p300 (EP300) regulated CRISP3 expression by affecting the H3K27ac modification of the CRISP3 promoter. In addition, knocking down EP300 curbed the malignant biological behavior of lobaplatin-resistant cells, which was antagonized by CRISP3 overexpression. Collectively, our results highlight the EP300/CRISP3 axis as a key driver of lobaplatin resistance in TNBC and suggest that therapeutic targeting of this axis may be an effective strategy for enhancing platinum sensitivity in TNBC., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

Piperazine is an important functional unit of many clinically approved drugs, including chemotherapeutic agents. In the current study, methyl piperazine was incorporated and eight salicylaldehyde-derived piperazine-functionalized hydrazone ONN-donor ligands (L) and their Pt(II) complexes (L-PtCl) were prepared. The structures of all these ligands (L1-L8) and Pt(II) complexes (C1-C8) were determined using 1 H and 13 C NMR, UV-vis, FT-IR and HR-ESI MS analyses, whereas the structures of C1, C5, C6, C7 and C8 were determined in the solid state using single crystal X-ray diffraction analysis. Solution state stabilities of C3, C4, C5 and C6 were determined via time-dependent UV-vis spectroscopy. All these complexes (C1-C8) were studied for their anticancer effect in pancreatic ductal adenocarcinoma cells, including BxPC3, MIAPaCa-2 and PANC1 cells. C1-C8 displayed a potential cytotoxic effect in all these cancer cells, among which C5, C6 and C8 showed the strongest inhibitory effect in comparison with standard chemotherapeutic agents, including 5-fluorouracil (5-FU), cisplatin (CP), oxaliplatin and doxorubicin (DOX). C5, C6 and C8 suppressed the growth of pancreatic cancer cells in a dose-dependent manner. Moreover, C5, C6 and C8 inhibited clonogenic potential and invasion ability and induced apoptosis in PANC1 cells. Importantly, C5, C6 and C8 synergized the anticancer effect with PARP inhibitors, including olaparib, veliparib and niraparib, in pancreatic cancer cells, thus suggesting an important role of C5, C6 and C8 in induction of apoptosis in combination with PARP inhibitors. C5 combined with PARP inhibitors induced caspase3/7 activity and suppressed ATP production. Mechanistically, C5, C6 and C8 inhibited EZH2 protein expression to suppress EZH2-dependent tumorigenesis. Overall, these results highlighted the importance of these piperazine-functionalized Pt(II) complexes as potential anticancer agents to suppress pancreatic ductal adenocarcinoma tumorigenesis by targeting the EZH2-dependent pathway.

Despite the investment in platinum drugs research, cisplatin, carboplatin and oxaliplatin are still the only Pt-based compounds used as first line treatments for several cancers, with a few other compounds being approved for administration in some Asian countries. However, due to the severe and worldwide impact of oncological diseases, there is an urge for improved chemotherapeutic approaches. Furthermore, the pharmaceutical application of platinum complexes is hindered by their inherent toxicity and acquired resistance. Nanodelivery systems rose as a key strategy to overcome these challenges, with recognized versatility and ability towards improving the safety, bioavailability and efficacy of the available drugs. Among the known nanocarriers, organic systems have been widely applied, taking advantage of their potential as drug vehicles. Researchers have mainly focused on the development of lipidic and polymeric carriers, including supramolecular structures, with an overall improvement of encapsulated platinum complexes. Herein, an overview of recent trends and strategies is presented, with the main focus on the encapsulation of platinum compounds into organic nanocarriers, showcasing the evolution in the design and development of these promising systems. This comprehensive review highlights formulation methods as well as characterization procedures, providing insights that may be helpful for the development of novel platinum nanocarriers aiming at future pharmaceutical applications.

In vitro tumor models were successfully constructed by 3D bioprinting; however, bioinks with proper viscosity, good biocompatibility, and tunable biophysical and biochemical properties are highly desirable for tumor models that closely recapitulated the main features of native tumors. Here, we developed a nanocomposite hydrogel bioink that was used to construct ovarian and colon cancer models by 3D bioprinting. The nanocomposite bioink was composed of aldehyde-modified cellulose nanocrystals (aCNCs), aldehyde-modified hyaluronic acid (aHA), and gelatin. The hydrogels possessed tunable gelation time, mechanical properties, and printability by controlling the ratio between aCNCs and gelatin. In addition, ovarian and colorectal cancer cells embedded in hydrogels showed high survival rates and rapid growth. By the combination of 3D bioprinting, ovarian and colorectal tumor models were constructed in vitro and used for drug screening. The results showed that gemcitabine had therapeutic effects on ovarian tumor cells. However, the ovarian tumor model showed drug resistance for oxaliplatin treatment.

Ovarian cancer has the worst case-to-fatality ratio of all gynecologic malignancies. The main reasons for the high mortality rate are relapse and the development of chemoresistance. In this paper, the cytotoxic activity of two new multiaction platinum(IV) derivatives of cisplatin and oxaliplatin in a panel of ovarian cancer cells is reported. Cis,cis,trans -[Pt(NH 3 ) 2 Cl 2 (IPA)(DCA)] ( 1 ) and trans -[Pt(DACH)(OX)(IPA)(DCA)] ( 2 ) (IPA = indole-3-propionic acid, DCA = dichloroacetate, DACH = 1R,2R -1,2-diaminocyclohexane, OX = oxalate) were synthesized and characterized by elemental analysis, ESI-MS, FT-IR, and 1 H, 13 C, and 195 Pt NMR spectroscopy. The biological activity was evaluated in A2780, PEA1, PEA2, SKOV3, SW626, and OVCAR3 cells. Both complexes are potent cytotoxins. Remarkably, complex 2 is 14 times more active in OVCAR3 cells than cisplatin and is able to overcome cisplatin resistance in PEA2 and A2780cis cells, which are models of post-treatment patient-developed and laboratory-induced resistance. This complex also shows activity in 3D cancer models of the A2780 cells. Mechanistic studies revealed that the complexes induce apoptosis via DNA damage and ROS generation.

Epithelial-mesenchymal transition (EMT) is a critical process for cancer progression, which is crucial in inhibiting the immunity in tumors and further boosting tumor metastasis. The suppression of EMT represents a promising strategy for inhibiting metastatic tumors. Herein, a series of new canadine platinum(IV) conjugates with potent antiproliferative and antimetastatic activities were developed, which activated by suppressing EMT and provoking immune response in tumors besides causing DNA injury. The complexes could covalently conjugate to DNA and induce mitochondria-mediated apoptosis via Bcl-2/Bax/caspase3 signaling. The EMT process was remarkably inhibited by suppressing the Wnt/β-catenin pathway, reversing the inflammatory tumor microenvironment, and inhibiting the HIF-1α pathway, which further resulted in the inhibited angiogenesis in tumors. Moreover, the antitumor immunity was elevated by blocking immune checkpoints PD-L1 and CD47 accompanied by the improvement of CD3 + and CD8 + T lymphocytes and the macrophage polarization from M2- toward M1-type simultaneously in tumors.

The hyphenation of HPLC with its high separation ability and ICP-MS with its excellent sensitivity, allows the analysis of Pt drugs in biological samples at the low nanomolar concentration levels. On the other hand, LC-MS provides molecular structural confirmation for each species. Using a combination of these methods, we have investigated the speciation of the photoactive anticancer complex diazido Pt(IV) complex trans , trans , trans -[Pt(N 3 ) 2 (OH) 2 (py) 2 ] (FM-190) in aqueous solution and biofluids at single-digit nanomolar concentrations before and after irradiation. FM-190 displays high stability in human blood plasma in the dark at 37 °C. Interestingly, the polyhydroxido species [{Pt IV (py) 2 (OH) 4 } + Na] + and [{Pt IV (py) 2 (N 3 )(OH) 3 } + Na] + resulting from the replacement of azido ligands, as determined by LC-MS, were the major products after photoirradiation of FM-190 with blue light (463 nm). This finding suggests that such photosubstituted Pt(IV) tri- and tetra-hydroxido species could play important roles in the biological activity of this anticancer complex. Density Functional Theory (DFT) and Time-Dependent DFT (TDDFT) calculations show that these Pt(IV) species arising from FM-190 in aqueous media can be formed directly from a singlet excited state. The results highlight how speciation analysis (metallomics) can shed light on photoactivation pathways for FM-190 and formation of potential excited-state pharmacophores. The ability to detect and identify photoproducts at physiologically-relevant concentrations in cells and tissues will be important for preclinical development studies of this class of photoactivatable platinum drugs.

The synthesis of three novel [C,N,N'] Pt(IV) cyclometallated compounds containing hydroxo, dichloroacetato or trifluoroacetato axial ligands is reported. Compound [PtCl(OH) 2 {(CH 3 ) 2 N(CH 2 ) 2 NCH(4-FC 6 H 3 )}] (3) was prepared by the oxidative addition of hydrogen peroxide to [C,N,N'] Pt(II) cyclometallated compound [PtCl{(CH 3 ) 2 N(CH 2 ) 2 NCH(4-FC 6 H 3 )}] (1) and further the reaction of compound 3 with dichloroacetate or trifluoroacetate anhydrides led to the formation of the corresponding compounds [PtCl(CHCl 2 COO) 2 {(CH 3 ) 2 N(CH 2 ) 2 NCH(4-FC 6 H 3 )}] (4) and [PtCl(CF 3 COO) 2 {(CH 3 ) 2 N(CH 2 ) 2 NCH(4-FC 6 H 3 )}] (5). The properties of the new compounds along with those of the compound [PtCl 3 {(CH 3 ) 2 N(CH 2 ) 2 NCH(4-FC 6 H 3 )}] (2), including stability in aqueous media, reduction potential using cyclic voltammetry, cytotoxic activity against the HCT116 CRC cell line, DNA interaction, topoisomerase I and cathepsin inhibition, and computational studies involving reduction of the Pt(IV) compounds and molecular docking studies, are presented. Interestingly, the antiproliferative activity of these compounds against the HCT116 CRC cell line, which is in all cases higher than that of cisplatin, follows the same trend as the reduction potentials so that the most easily reduced compound 2 is the most potent. In contrast, according to the electrophoretic mobility and molecular docking studies, the efficacy of these compounds in binding to DNA is not related to their cytotoxicity. The most active compound 2 does not modify the DNA electrophoretic mobility while the less potent compound 3 is the most efficient in binding to DNA. Although compounds 2 and 3 have only a slight effect on cell cycle distribution and apoptosis induction, generation of ROS to a higher extent for the most easily reduced compound 2 was observed.

The history of effective anti-cancer medications begins with the discovery of cisplatin's anti-cancer properties. Second-generation analogue, carboplatin, with a similar range of effectiveness, made progress in improving these drugs with fewer side effects and better solubility. Renewed interest in platinum-based drugs has been increasing in the past several years. These developments highlight a revitalized enthusiasm and ongoing exploration in platinum chemotherapy based on the series of dinuclear platinum(II) complexes, [{Pt(L)Cl} 2 ( μ -bridging ligand)] 2+ , which have been synthesized and evaluated for their biological activities. These complexes are designed to target various cancerous conditions, exhibiting promising antitumor, antiproliferative, and apoptosis-inducing activities. The current work aims to shed light on the potential of these complexes as next-generation platinum-based therapies, highlighting their enhanced efficacy and reduced side effects, which could revolutionize the approach to chemotherapy.

Extracellular vesicles (EVs), exhibiting their functional activity after internalization by recipient cells, are involved in the pathogenesis of drug-induced polyneuropathy (DIPN), a common complication of antitumor therapy. In this work, the internalization of EVs obtained from colorectal cancer patients undergoing polychemotherapy and its relationship with neurotoxicity were assessed using a model system of mononuclear leukocytes. Circulating EVs were isolated from 8 colorectal cancer patients who received antitumor therapy according to the FOLFOX or XELOX regimens before the start of chemotherapy (point 1) and after 3-4 courses (point 2). Mononuclear leukocytes of a healthy donor served as a cellular model system for EV internalization in vitro. EV internalization was assessed using fluorescence microscopy. It was shown that internalization of EVs obtained from colorectal cancer patients with high neurotoxicity was higher than in the group with low neurotoxicity. The ability of CD11b-positive (CD11b⁺) and CD11b-negative (CD11b⁻) mononuclear leukocytes of a healthy donor to internalize EVs obtained from patients before and after chemotherapy did not reveal significant differences. A direct relationship was found between the relative number of CD11b⁻ cells with internalized EVs and the integral index of neurotoxicity according to the NRS scale at the peak of its manifestation (point 2) (r=0.675, p.

Background/aim: Platinum-based chemotherapies are a component of standard-of-care regimens for urothelial carcinoma (UC). These nephrotoxic drugs are often dose-limiting, with cisplatin and carboplatin being the most commonly used. Dicycloplatin (DCP) has better solubility and stability, with comparable efficacy and better tolerability. Some suggest the use of DCP as primary treatment for non-muscle-invasive bladder cancer. We exposed UC cell lines to DCP in vitro to assess its efficacy., Materials and Methods: A high grade (IV) in vitro UC cell line (TCCSUP) was exposed to varying concentrations of cisplatin (0-600 μg/ml), carboplatin (0-600 μg/ml), oxaliplatin (0-4.0 μg/ml), and DCP (0-350 μg/ml). Grade II-IV cells were exposed to varying concentrations of DCP (0-350 μg/ml) to assess time- and concentration-dependent growth inhibition, and simulate intravesical treatment. Growth inhibition was determined following 24, 48, and 72 h of exposure, using a tetrazolium dye to assess mitochondrial dehydrogenase activity., Results: DCP, cisplatin, and carboplatin effectively achieved >90% cell kill at 72 h. Concentrations of 325 μg/ml DCP, 50 μg/ml cisplatin, and 600 μg/ml carboplatin were sufficient for >90% cell-kill, with cisplatin demonstrating the highest efficacy at the lowest concentration/time intervals. Dose- and time-dependent cell kill were demonstrated at varying concentrations of DCP in grade II-IV cell lines, including cells exposed intravesically., Conclusion: In vitro, DCP demonstrates cell-killing efficacy in a time- and concentration-dependent manner in grade II-IV UC cell lines, showing promise for its intravenous, oral, and intravesical use for bladder UC in both primary and adjuvant/neoadjuvant settings., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Palladium and platinum complexes, especially those that include cisplatin, can be useful chemotherapeutic drugs. Alternatives that have less adverse effects and require lower dosages of treatment could be provided by complexes containing pyridine bases. The complexes [Pd(SCN) 2 (4-Acpy) 2 ] (1), [Pd(N 3 ) 2 (4-Acpy) 2 ] (2) [Pd(paOH) 2 ].2Cl (3) and [Pt(SCN) 2 (paO) 2 ] (4) were prepared by self-assembly method at ambient temperature; (4-Acpy = 4-acetylpyridine and paOH = pyridine-2-carbaldehyde-oxime). The structure of complexes 1-4 was confirmed using spectroscopic and X-ray crystallography methods. Complexes 1-4 have similar features in isomerism that include the trans coordination geometry of pyridine ligands with Pd or Pt ion. The 3D network structure of complexes 1-4 was constructed by an infinite number of discrete mononuclear molecules extending via H-bonds. The Pd and Pt complexes 1-4 with pyridine ligands were assessed on MCF-7, T47D breast cancer cells and HCT116 colon cancer cells. The study evaluated cell death through apoptosis and cell cycle phases in MCF-7 cells treated with palladium or platinum conjugated with pyridine base. Upon treatment of MCF-7 with these complexes, the expression of apoptotic signals (Bcl2, p53, Bax and c-Myc) and cell cycle signals (p16, CDK1A, CDK1B) were evaluated. Compared to other complexes and cisplatin, IC 50 of complex 1 was lowest in MCF-7 cells and complex 2 in T47D cells. Complex 4 has the highest effectiveness on HCT116. The selective index (SI) of complexes 1-4 has a value of more than two for all cancer cell lines, indicating that the complexes were less toxic to normal cells when given the same dose. MCF-7 cells treated with complex 2 and platinum complex 4 exhibited the highest level of early apoptosis. p16 may be signal arrest cells in Sub G, which was observed in cells treated with palladium complexes that suppress excessive cell proliferation. High c-Myc expression of treated cells with four complexes 1-4 and cisplatin could induce p53. All complexes 1-4 elevated the expression of Bax and triggered by the tumor suppressor gene p53. p53 was downregulating the expression of Bcl2., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Here, we report a photodynamic therapy (PDT) photosensitizer of N ∧ C ∧ N-coordinated Pt(II) complexes: [Pt(L)(solv)] + (HL = 1,3-(2-dipyridyl)benzene) and [Pt(L)] + @HSA, which is the Pt(II) complex encapsulated in human serum albumin (HSA). The quantum yield of singlet oxygen production for [Pt(L)(solv)] + is more than 50%, while that for [Pt(L)] + @HSA is much lower. Photoimages of human umbilical vein endothelial cells (HUVECs) treated with the Pt(II) complexes suggest that [Pt(L)(solv)] + is delocalized in the entire cell after the fast uptake by diffusion and [Pt(L)] + @HSA is taken up by endocytosis and localized on organelles and the cell membrane. [Pt(L)(solv)] + shows high photocytotoxicity for HUVECs, while [Pt(L)] + @HSA does not show photocytotoxicity.

Gastric cancer prognosis is still notably poor despite efforts made to improve diagnosis and treatment of the disease. Chemotherapy based on platinum agents is generally used, regardless of the fact that drug toxicity leads to limited clinical efficacy. In order to overcome these problems, our group has been working on the synthesis and study of trans platinum (II) complexes. Here, we explore the potential use of two phosphine-based agents with the general formula trans -[Pt(amine)Cl 2 (PPh 3 )], called P1 and P2 (with dimethylamine or isopropylamine, respectively). A cytotoxicity analysis showed that P1 and especially P2 decrease cell viability. Specifically, P2 exhibits higher activity than cisplatin in gastric cancer cells while its toxicity in healthy cells is slightly lower. Both complexes generate Reactive Oxygen Species, produce DNA damage and mitochondrial membrane depolarization, and finally lead to induced apoptosis. Thus, an intrinsic apoptotic pathway emerges as the main type of cell death through the activation of BAX/BAK and BIM and the degradation of MCL1. Additionally, we demonstrate here that P2 produces endoplasmic reticulum stress and activates the Unfolded Protein Response, which also relates to the impairment observed in autophagy markers such as p62 and LC3. Although further studies in other biological models are needed, these results report the biomolecular mechanism of action of these Pt(II)-phosphine prototypes, thus highlighting their potential as novel and effective therapies.

Platinum-based chemotherapeutic agents are widely used in the treatment of cancer. However, their effectiveness is limited by severe adverse reactions, drug resistance, and poor water solubility. This study focuses on the synthesis and characterization of new water-soluble cationic monofunctional platinum(II) complexes starting from the [PtCl(η 1 -C 2 H 4 OEt)(phen)] (1, phen=1,10-phenanthroline) precursor, specifically [Pt(NH 3 )(η 1 -C 2 H 4 OEt)(phen)]Cl (2), [Pt(1-hexyl-1H-imidazole)(η 1 -C 2 H 4 OEt)(phen)]Cl (3), and [Pt(1-hexyl-1H-benzo[d]imidazole)(η 1 -C 2 H 4 OEt)(phen)]Cl (4), which deviate from traditional requirements for antitumor activity. These complexes were evaluated for their cytotoxic effects in comparison to cisplatin, using immortalized cervical adenocarcinoma cells (HeLa), human renal carcinoma cells (Caki-1), and normal human renal cells (HK-2). While complex 2 showed minimal effects on the cell lines, complexes 3 and 4 demonstrated higher cytotoxicity than cisplatin. Notably, complex 4 displayed the highest cytotoxicity in both cancer and normal cell lines. However, complex 3 exhibited the highest selectivity for renal tumor cells (Caki-1) among the tested complexes, compared to healthy cells (HK-2). This resulted in a significantly higher selectivity than that of cisplatin and complex 4. Therefore, complex 3 shows potential as a leading candidate for the development of a new generation of platinum-based anticancer drugs, utilizing biocompatible imidazole ligands while demonstrating promising anticancer properties., (© 2024 Wiley-VCH GmbH.)

It is generally accepted that adjacent guanine residues in DNA are the primary target for platinum antitumor drugs and that differences in the conformations of the Pt-DNA adducts can play a role in their antitumor activity. In this study, we investigated the effect of the carrier ligand cis -1,3-diaminocyclohexane ( cis -1,3-DACH) upon formation, stability, and stereochemistry of the ( cis -1,3-DACH)PtG 2 and ( cis -1,3-DACH)Pt(d(GpG)) adducts (G = 9-EthlyGuanine, guanosine, 5'- and 3'-guanosine monophosphate; d(GpG) = deoxyguanosil(3'-5')deoxyguanosine). A peculiar feature of the cis -1,3-DACH carrier ligand is the steric bulk of the diamine, which is asymmetric with respect to the Pt-coordination plane. The ( cis -1,3-DACH)Pt(5'GMP) 2 and ( cis -1,3-DACH)Pt(3'GMP) 2 adducts show preference for the ΛHT and ∆HT conformations, respectively (HT stands for Head-to-Tail). Moreover, the increased intensity of the circular dichroism signals in the cis -1,3-DACH derivatives with respect to the analogous cis -(NH 3 ) 2 species could be a consequence of the greater bite angle of the cis -1,3-DACH carrier ligand with respect to cis -(NH 3 ) 2 . Finally, the ( cis -1,3-DACH)Pt(d(GpG)) adduct is present in two isomeric forms, each one giving a pair of H8 resonances linked by a NOE cross peak. The two isomers were formed in comparable amounts and had a dominance of the HH conformer but with some contribution of the ΔHT conformer which is related to the HH conformer by having the 3'-G base flipped with respect to the 5'-G residue.

The study aims to synthesize a novel bis(thiosemicarbazone) derivative based on platinum (thioPt) and evaluate its anticancer properties against MFC-7 and MDA-MB-231 breast cancer cells. A new platinum complex was synthesised by reacting K 2 PtCl 4 with 2,2'-(1,2-diphenylethane-1,2-diylidene)bis(hydrazine-1-carbothioamide) in ethanol in the presence of K 2 CO 3 . In the obtained complex, the platinum atom is coordinated by a conjugated system = N-NC-S-The structures of the new compound were characterised using NMR spectroscopy, HR MS, IR, and X-ray structural analysis. The obtained results of the cytotoxicity assay indicate that compound thioPt had potent anticancer activity (MCF-7: 61.03 ± 3.57 µM, MDA-MB-231: 60.05 ± 5.40 µM) with less toxicity against normal MCF-10A breast epithelial cells, even compared to the reference compound (cisplatin). In addition, subsequent experiments found that thioPt induces apoptosis through both an extrinsic (↑caspase 8 activity) and intrinsic (↓ΔΨ m ) pathway, which ultimately leads to an increase in active caspase 3/7 levels. The induction of autophagy and levels of proteins involved in this process (LC3A/B and Beclin-1) were examined in MCF-7 and MDA-MB-231 breast cancer cells exposed to tested compounds (thio, thioPt, cisPt) at a concentration of 50 µM for 24 h. Based on these results, it can be concluded that thio and thioPt do not significantly affect the autophagy process. This demonstrates their superiority over cisplatin, which can stimulate cancer cell survival through its effect on stimulation of autophagy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Liposomes carrying chemotherapeutic drugs can accumulate passively in solid tumors at high levels. However, additional targeting of the liposomes towards e.g. receptors expressed on cancer cells may improve their interaction and therapeutic properties. In this study, we designed a liposomal delivery system, which utilizes the intrinsic characteristics of HER2-positive tumors to ensure efficient delivery of oxaliplatin to the cancer cells. On the liposome surface, trastuzumab, an antibody specific to the HER2 receptor, was shown to facilitate internalization by the cancer cells. A polyethylene glycol (PEG) layer on the liposome surface provides protection from mononuclear phagocyte system uptake. To optimize the interaction between liposomes and cancer cells, a protease-sensitive cleavable peptide linker was inserted at the base of each PEG. The PEG layer is then cleaved off by intra- and extracellular matrix metalloproteinases (MMPs) upon accumulation in the tumor. Our data demonstrate that the removal of PEG significantly destabilizes the liposomes and leads to substantial oxaliplatin release. The proposed beneficial effect of combining antibody-mediated internalization with MMP sensitivity was confirmed in a series of in vivo studies using ovarian cancer xenograft models. The results demonstrated that HER2-targeted MMP-sensitive liposomes have superior anticancer activity compared to non-targeted and non-cleavable liposomes., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Background: The key endpoints for the assessment of the effect of maintenance therapy for metastatic colorectal cancer (mCRC) are survival and quality-of-life outcomes. We aimed to compare dermatology-related quality of life (DRQOL) in patients with RAS wild-type (wt) mCRC treated with fluorouracil and folinic acid (FU/FA) + panitumumab (Pmab) versus FU/FA alone as maintenance therapy after folinic acid, fluorouracil and oxaliplatin + Pmab induction., Patients and Methods: The phase II randomized PanaMa (AIO KRK 0212; NCT01991873) trial included 387 patients at 70 community/academic sites in Germany. For this prespecified secondary analysis, DRQOL outcomes were assessed using the Functional Assessment of Cancer Therapy-epidermal growth factor receptor inhibitor (FACT-EGFRI), Dermatology Life Quality Index (DLQI), and Skindex-16 questionnaires at every second cycle of therapy until disease progression/death., Results: At least one DRQOL questionnaire was completed by a total of 310/377 (82%) patients who received induction therapy, and by 216/248 (87%) patients who were randomized and received maintenance therapy. Patients who experienced skin toxicity according to the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) during induction therapy had significantly worse DRQOL according to all three measures, compared to those who did not [i.e. Skindex-16, mean difference at cycle 2 -12.87; 95% confidence interval (CI) -20.01 to -5.73; P < 0.001]. During maintenance therapy, significantly improved recovery was observed in all DRQOL measures for patients receiving FU/FA, compared to those receiving additional Pmab (i.e. Skindex-16, mean difference at cycle 6 -16.53; 95% CI -22.68 to -10.38; P < 0.001)., Conclusions: In this secondary analysis of a phase II randomized clinical trial, patient-reported DRQOL outcomes correlated with skin toxicity according to NCI-CTCAE during induction therapy. Maintenance therapy with FU/FA + Pmab was associated with deteriorated DRQOL versus FU/FA alone in patients with RAS wt mCRC., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Herby, the interaction of metallothioneins with commonly used Pt-based anticancer drugs - cisplatin, carboplatin, and oxaliplatin - was investigated using the combined power of elemental (i.e. LA-ICP-MS, CE-ICP-MS) and molecular (i.e. MALDI-TOF-MS) analytical techniques providing not only required information about the interaction, but also the benefit of low sample consumption. The amount of Cd and Pt incorporated within the protein was determined for protein monomers and dimer/oligomers formed by non-oxidative dimerization. Moreover, fluorescence spectrometry using Zn 2+ -selective fluorescent indicator - FluoZin3 - was employed to monitor the ability of Pt drugs to release natively occurring Zn from the protein molecule. The investigation was carried out using two protein isoforms (i.e. MT2, MT3), and significant differences in behaviour of these two isoforms were observed. The main attention was paid to elucidating whether the protein dimerization/oligomerization may be the reason for the potential failure of the anticancer therapy based on these drugs. Based on the results, it was demonstrated that the interaction of MT2 (both monomers and dimers) interacted with Pt drugs significantly less compared to MT3 (both monomers and dimers). Also, a significant difference between monomeric and dimeric forms (both MT2 and MT3) was not observed. This may suggest that dimer formation is not the key factor leading to the inactivation of Pt drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Oxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting toxicity characterised by mechanical allodynia and thermal hyperalgesia, without any licensed medications. ART26.12 is a fatty acid-binding protein (FABP) 5 inhibitor with antinociceptive properties, characterised here for the prevention and treatment of OIPN. ART26.12 binds selectively to FABP5 compared to FABP3, FABP4, and FABP7, with minimal off-target liabilities, high oral bioavailability, and a NOAEL of 1,000 mg/kg/day in rats and dogs. In an established preclinical OIPN model, acute oral dosing (25-100 mg/kg) showed a cannabinoid receptor type 1 (CB 1 )-dependent anti-allodynic effect lasting up to 8 hours (persisting longer than plasma exposure to ART26.12). Antagonists of cannabinoid receptor type 2 (CB 2 ), peroxisome proliferator-activated receptor alpha, and transient receptor potential cation channel subfamily V member 1 (TRPV1) may have also been implicated. Twice daily oral dosing (25 mg/kg bis in die (BID) for 7 days) showed anti-allodynic effects in an established OIPN model without the development of tolerance. In a prevention paradigm, coadministration of ART26.12 (10 and 25 mg/kg BID for 15 days) with oxaliplatin prevented thermal hyperalgesia, mitigated mechanical allodynia, and attenuated OXA-induced weight loss. Multi-scale analyses revealed widespread lipid modulation, particularly among N-acyl amino acids in the spinal cord, including potential analgesic mediators. Additionally, ART26.12 administration led to upregulation of ion channels in the periaqueductal grey, and broad translational upregulation within the plasma proteome. These results show promise that ART26.12 is a safe and well-tolerated candidate for the treatment and prevention of OIPN through lipid modulation. PERSPECTIVE: Inhibition of fatty acid-binding protein 5 (FABP5) is a novel target for reducing pain associated with chemotherapy. ART26.12 is a safe and well-tolerated small molecule FABP5 inhibitor effective at preventing and reducing pain induced with oxaliplatin through lipid modulation and activation of cannabinoid receptors., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

In this project, to fallow the anticancer ability of new Pt drugs, several new Pt complexes were synthesized with the asymmetric bidentate glycine derivatives, as named propyl- and hexyl glycine (L), in the general formula: [Pt(NH 3 ) 2 (L)]NO 3 , and cis- and trans-[Pt(L) 2 ]. The structure of two cis- and trans-[Pt(propylgly) 2 ] complexes was proved by single crystallography analysis. However, all complex structures were characterized by various methods of 1 H NMR, 13 C NMR, 195 Pt NMR, FTIR, LC-Mass, and Raman spectroscopy. To study the passage of water-soluble complexes of [Pt(NH 3 ) 2 (L)]NO 3 via cell membrane, their solubility, and lipophilicity were analyzed. In addition, the cytotoxic properties of these complexes were evaluated against normal and malignant cell lines (skin, breast, and lung cancer cells). The results indicated that they were either comparable to cisplatin or less damaging than carboplatin and oxaliplatin. It was expected that due to less steric effect, and the presence of length aliphatic hydrocarbon chain in the complex structure, trans-[Pt(hexylgly) 2 ] is more toxic on cancerous cell lines than trans-[Pt(propylgly) 2 ]. Cellular accumulation of all complexes was evaluated on A549 and MCF7 cell lines, and the amount of platinum metal (ng) was measured by the ICP method. Results showed that trans-[Pt(hexylgly) 2 ] complex has the highest accumulation inside both mentioned cell lines and [Pt(NH 3 ) 2 (L)]NO 3 complexes behave like clinical Pt-drugs. Ultimately, the interaction patterns of DNA were examined using spectroscopic methods and molecular docking simulations for all substances., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In the upcoming decades, the incidence and mortality rates of cancer are expected to rise globally, with colorectal and prostate cancers among the most prevalent types. Despite advancements in molecular targeted therapy, platinum-based chemotherapies remain the cornerstone of treatment, especially for colorectal and prostate cancer, with oxaliplatin and cisplatin being extremely effective due to their DNA-targeting capabilities. In our pursuit of new platinum-based chemotherapeutics that are potentially less toxic and more effective, we have explored the combination of the Pt-binding groups of the diaminocyclohexane ring used in oxaliplatin, with the stable amino-pyrimidine hemicurcumin moiety. This new derivative exhibit improved stability in physiological conditions and increased solubility in aqueous media, demonstrating promising effects on cell proliferation of both colorectal and prostate cells. We report herein the complete synthesis and chemical characterization in solution of the new derivative [(1R,2R)-N1-(3-(4-((E)-2-(2-Amino-6-methylpyrimidin-4-yl)vinyl)-2-methoxyphenoxy) propyl) cyclohexane-1,2-diamine] (MPYD). Our analysis includes an examination of its acid-base equilibria, speciation and stability in physiological conditions. The synthesis and in situ formation of Pt(II) complexes were investigated by nuclear magnetic resonance spectroscopy, while density functional theory calculations were employed to elucidate the chemical structure in solution. Results on the biological activity were obtained through cell viability assays on different colorectal and prostate cell lines (HCT116, HT29, PC3 and LNCaP)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Platinum-based anticancer drugs have been at the forefront of cancer chemotherapy, with cisplatin emerging as a pioneer in the treatment of various malignancies. This review article provides a comprehensive overview of the evolution of platinum-based anticancer therapeutics, focusing on the development of cisplatin, platinum(IV) prodrugs, and the integration of photodynamic therapy (PDT) for enhanced cancer treatment results. The first section of the review delves into the historical context and molecular mechanisms underlying the success of cisplatin, highlighting its DNA binding properties and subsequent interference with cellular processes. Despite its clinical efficacy, the inherent limitations, including dose-dependent toxicities and acquired resistance, accelerated the exploration of novel platinum derivatives. This led to the emergence of platinum(IV) prodrugs, designed to overcome resistance mechanisms and enhance selectivity through targeted drug delivery. The subsequent section provides an in-depth analysis of the principles of design and structural modifications employed in the development of platinum(IV) prodrugs. The transitions to the incorporation of photodynamic therapy (PDT) stands out as a synergistic approach to platinum-based anticancer treatment. The photophysical properties of platinum complexes are discussed in the context of their potential application in PDT, emphasizing on combined cytotoxic effects of platinum-based drugs and light-induced reactive oxygen species generation. This dual-action approach holds great promise for overcoming the limitations of traditional chemotherapy as well as producing superior therapeutic outcomes. Overall, the present report explores the latest developments in the development and use of platinum complexes, highlighting novel strategies such combination treatments, targeted delivery methods, and the generation of multifunctional complexes. It also provides a comprehensive overview of the current landscape while proposing future directions for the development of next-generation platinum-based anticancer therapeutics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In search of potential anticancer agents, we synthesized SNO-donor salicylaldimine main ligand-based Pt(II) complexes bearing NH 3 as co-ligand at trans-position (C1-C6). These complexes showed similarity in structure with transplatin as the two N donor atoms of the main ligand and NH 3 co-ligand were coordinated to Pt in trans position to each other. Each complex with different substituents on the main ligand was characterized thoroughly by detailed spectroscopic and spectrophotometric methods. Four of these complexes were studied in solid state by single crystal X-ray analysis. The stability of reference complex C1 was measured in solution state in DMSO‑d 6 or its mixture with D 2 O using 1 H NMR methods. These complexes were further investigated for their anticancer activity in triple-negative-breast (TNBC) cells including MDA-MB-231, MDA-MB-468 and MDA-MB-436 cells. All these complexes showed satisfactory cytotoxic effect as revealed by the MTT results. Importantly, the highly active complex C4 anticancer effect was compared to the standard chemotherapeutic agents including cisplatin, oxaliplatin and 5-fluorouracil (5-FU). Functionally, C4 suppressed invasion, spheroids formation ability and clonogenic potential of cancer cells. C4 showed synergistic anticancer effect when used in combination with palbociclib, JQ1 and paclitaxel in TNBC cells. Mechanistically, C4 inhibited cyclin-dependent kinase (CDK)4/6 pathway and targeted the expressions of MYC/STAT3/CCND1/CNNE1 axis. Furthermore, C4 suppressed the EMT signaling pathway that suggested a role of C4 in the inhibition of TNBC metastasis. Our findings may pave further in detailed mechanistic study on these complexes as potential chemotherapeutic agents in different types of human cancers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Oxaliplatin-based chemotherapy has proven to be one of the most effective treatments for advanced or metastatic colorectal cancer. However, increasing clinical resistance to oxaliplatin poses unprecedented challenges for both patients and clinicians. Despite extensive efforts to combat this issue, to date, no new molecules have been discovered that can successfully replace oxaliplatin. With the aim of developing a new generation of Pt(II)-based anticancer agents in response to the challenges of oxaliplatin-induced drug resistance, we performed a systematic screening of new Pt(II)-complexes with a quantitative structure-activity relationship (QSAR) study based on their antiresistance activity against oxaliplatin-resistant colon cancer cells. The results revealed that both the structure and chirality of the chelating ligand had a significant impact on the antiresistance properties of the Pt(II)-complexes. Our study culminated in the identification of chiral R -binaphthyldiamine-ligated Pt(II)-malonatoglycoconjugates that can completely counteract oxaliplatin resistance with excellent in vitro and in vivo potency.

Cell senescence is defined as irreversible cell cycle arrest, which can be triggered by telomere shortening or by various types of genotoxic stress. Induction of senescence is emerging as a new strategy for the treatment of cancer, especially when sequentially combined with a second senolytic drug capable of killing the resulting senescent cells, however severely suffering from the undesired off-target side effects from the senolytic drugs. Here, we prepare a bimetalic platinum-aluminum salen complex (Alumiplatin) for cancer therapy-a combination of pro-senesence chemotherapy with in situ senotherapy to avoid the side effects. The aluminum salen moiety, as a G-quadruplex stabilizer, enhances the salen's ability to induce cancer cell senescence and this phenotype is in turn sensitive to the cytotoxic activity of the monofunctional platinum moiety. It exhibits an excellent capability for inducing senescence, a potent cytotoxic activity against cancer cells both in vitro and in vivo, and an improved safety profile compared to cisplatin. Therefore, Alumiplatin may be a good candidate to be further developed into safe and effective anticancer agents. This novel combination of cell senescence inducers with genotoxic drugs revolutionizes the therapy options of designing multi-targeting anticancer agents to improve the efficacy of anticancer therapies., (© 2024 Wiley-VCH GmbH.)

While a number of p53-MDM2 inhibitors have progressed into clinical trials for the treatment of cancer, their progression has been hampered by a variety of problems, including acquired drug resistance, dose-dependent toxicity, and limited clinical efficiency. To make more progress, we integrated the advantages of MDM2 inhibitors and platinum drugs to construct novel Pt IV -RG7388 (a selective MDM2 inhibitor) complexes. Most complexes, especially 5a and 5b , displayed greatly improved antiproliferative activity against both wild-type and mutated p53 cancer cells. Remarkably, 5a exhibited potent in vivo tumor growth inhibition in the A549 xenograft model (66.5%) without apparent toxicity. It arrested the cell cycle at both the S phase and the G2/M phase and efficiently induced apoptosis via the synergistic effects of RG7388 and cisplatin. Altogether, Pt IV -RG7388 complex 5a exhibited excellent in vitro and in vivo antitumor activities, highlighting the therapeutic potential of Pt IV -RG7388 complexes as antitumor agents.

Herein, we describe the general design, synthesis, characterization, and biological activity of new multitargeting Pt(IV) prodrugs that combine antitumor cisplatin and dasatinib, a potent inhibitor of Src kinase. These prodrugs exhibit impressive antiproliferative and anti-invasive activities in tumor cell lines in both two-dimensional (2D) monolayers of cell cultures and three-dimensional (3D) spheroids. We show that the cisplatin moiety and dasatinib in the investigated Pt(IV) complexes are both involved in the mechanism of action in MCF7 breast cancer cells and act synergistically. Thus, combining dasatinib and cisplatin into one molecule, compared to using individual components in a mix, may bring several advantages, such as significantly higher activity in cancer cell lines and higher selectivity for tumor cells. Most importantly, Pt(IV)-dasatinib complexes hold significant promise for potential anticancer therapies by targeting epithelial-mesenchymal transition, thus preventing the spread and metastasis of tumors, a value unachievable by a simple combination of both individual components.

Monofunctional platinum complexes offer a promising alternative to cisplatin in cancer chemotherapy, showing a unique mechanism of action. Their ability to induce minor helix distortions effectively inhibits DNA transcription. In our study, we synthesized and characterized three monofunctional Pt(II) complexes with the general formula [Pt(en)(L)Cl]NO 3 , where en = ethylenediamine, and L = pyridine (py), 2-methylpyridine (2-mepy), and 2-phenylpyridine (2-phpy). The hydrolysis rates of [Pt(en)(py)Cl]NO 3 ( 1 ) and [Pt(en)(2-mepy)Cl]NO 3 ( 2 ) decrease with the bulkiness of the auxiliary ligand with k( 1 ) = 2.28 ± 0.15 × 10 -4 s -1 and k( 2 ) = 8.69 ± 0.98 × 10 -5 s -1 at 298 K. The complex [Pt(en)(2-phpy)Cl]Cl ( 3 ) demonstrated distinct behavior. Upon hydrolysis, an equilibrium (K eq = 0.385 mM) between the complexes [Pt(en)(2-phpy)Cl] + and [Pt(en)(2-phpy-H + )] + was observed with no evidence (NMR or HR-ESI-MS) for the presence of the aquated complex [Pt(en)(2-phpy)(H 2 O)] 2+ . Despite the kinetic similarities between phenanthriplatin and ( 2 ), complexes ( 1 ) and ( 2 ) exhibit minimal activity against A549 lung cancer cell line (IC 50 > 100 μΜ), whereas complex ( 3 ) exhibits notable cytotoxicity (IC 50 = 41.11 ± 2.1 μΜ). In examining the DNA binding of ( 1 ) and ( 2 ) to the DNA model guanosine (guo), we validated their binding through guoN7, which led to an increased population of the C3'- endo sugar conformation, as expected. However, we observed that the rapid transition 2 E (C2' -endo ) ↔ 3 E (C3' -endo ), in the case of [Pt(en)(py)(guo)](NO 3 ) 2 ([ 1 -guo]), slows down in the case of [Pt(en)(2-mepy)(guo)](NO 3 ) 2 ([ 2 -guo]), resulting in separate signals for the two conformers in the 1 H NMR spectra. This phenomenon arises from the steric hindrance between the methyl group of pyridine and the sugar moiety of guanosine. Notably, this hindrance is absent in [ 2 -(9-MeG)] (9-MeG = 9-methylguanine), probably due to the absence of a bulky sugar unit in 9-MeG. In the case of ( 3 ), where the bulkiness of the substitution on the pyridine is further increased by a phenyl group, we observed a notable proximity between 9-MeGH8 and the phenyl ring of 2-phpy. Considering that only ( 3 ) exhibited good cytotoxicity against the A549 cancer cell line, it is suggested that auxiliary ligands, L, with an extended aromatic system and proper orientation in complexes of the type cis-[Pt(en)(L)Cl]NO 3 , may enhance the cytotoxic activity of such complexes.

Background/aim: Apoptosis resistance in cancer cells adapted to acidic microenvironments poses a challenge for effective treatment. This study investigated the potential use of caffeic acid as an adjunct therapy to overcome drug resistance in colorectal cancer cells under acidic conditions., Materials and Methods: Long-term exposure to low-pH conditions induced resistance in HCT116 colorectal cancer cells. The effects of caffeic acid on proliferation, clonogenicity, and apoptosis induction were assessed alone and in combination with oxaliplatin and 5-Fluorouracil. The signaling pathways involved in drug resistance were examined by assessing the activities of PI3K/Akt and ERK1/2., Results: Caffeic acid inhibited the proliferation and clonogenicity of acid-adapted cancer cells, and enhanced apoptosis when combined with anticancer drugs. Mechanistically, caffeic acid attenuated the hyperactivation of the PI3K/Akt and ERK1/2 signaling pathways associated with drug resistance., Conclusion: Caffeic acid is a promising therapeutic agent for targeting resistant cancer cells in acidic microenvironments. Its ability to inhibit proliferation, sensitize cells to apoptosis, and modulate signaling pathways highlights its potential for overcoming drug resistance in cancer therapy., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: The incidence of primary liver cancer (PLC) has experienced a significant global increase, primarily attributed to the rise in hepatocellular carcinoma (HCC). Unfortunately, HCC is often diagnosed in advanced stages, leaving patients with limited treatment options. Therefore, transformation therapy is a crucial approach for long-term survival and radical resection in patients with advanced HCC. Conversion therapy has demonstrated promise in the treatment of advanced HCC. When integrated with the FOLFOX regimen, hepatic artery infusion chemotherapy (HAIC) can significantly improve tumor response efficiency, leading to high conversion and resection rates., Areas Covered: We reviewed landmark trials of HAIC in combination with different drugs or means for the treatment of HCC to determine the clinical value of HAIC-centric translational therapies in HCC treatment. Furthermore, we specifically emphasize the advantages associated with employing FOLFOX-HAIC in the treatment of advanced HCC., Expert Opinion: The combination of HAIC with the FOLFOX regimen can help prevent the low intratumoral accumulation and high adverse reaction rate caused by the FOLFOX alone, holding significant potential in the comprehensive treatment of future HCC patients.

Esophageal squamous cell carcinoma (ESCC) is a malignant tumor that is highly susceptible to metastasis, recurrence and resistance, and few therapeutic targets have been identified and proven effective. Herein, we demonstrated for the first time that Rap1b can positively regulate ESCC cell stemness, as well as designed and synthesized a novel class of Pt(IV) complexes that can effectively inhibit Raplb. In vitro biological studies showed that complex-1 exhibited stronger cytotoxicity than cisplatin and oxaliplatin against a variety of ESCC cells, and effectively reversed cisplatin-induced resistance of TE6 cells by increasing cellular accumulation of platinum and inhibiting cancer cell stemness. Significantly, complex-1 also exhibited strong ability to reversal cisplatin-induced cancer cell resistance and inhibit tumor growth in TE6/cDDP xenograft mice models, with a tumor growth inhibition rate of 73.3 % at 13 mg/kg and did not show significant systemic toxicity. Overall, Rap1b is a promising target to be developed as an effective treatment for ESCC. Complex-1, as the first Pt(IV) complex that can strongly inhibit Rap1b, is also worthy of further in-depth study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cyclometallated Pt(II) complexes possessing hydrophobic 2-phenylpyridine (ppy) ligands and hydrophilic acetonylacetone (acac) ligands have been investigated for their ability to detect amyloid fibrils via luminescence response. Using hen egg-white lysozyme (HEWL) as a model amyloid protein, Pt(II) complexes featuring benzanilide-substituted ppy ligands and ethylene glycol-functionalized acac ligands demonstrated enhanced luminescence in the presence of HEWL fibrils, whereas Pt(II) complexes lacking complementary hydrophobic/hydrophilic ligand sets displayed little to no emission enhancement. An amphiphilic Pt(II) complex incorporating a bis(ethylene glycol)-derivatized acac ligand was additionally found to trigger restructuring of HEWL fibrils into smaller spherical aggregates. Amphiphilic Pt(II) complexes were generally non-toxic to SH-SY5Y neuroblastoma cells, and several complexes also exhibited enhanced luminescence in the presence of Aβ 42 fibrils associated with Alzheimer's disease. This study demonstrates that easily prepared and robust (ppy)Pt II (acac) complexes show promising reactivity toward amyloid fibrils and represent attractive molecular scaffolds for design of small-molecule probes targeting amyloid assemblies.

Promising targeted therapy options to overcome drug resistance and side effects caused by platinum(II) drugs for treatment in hepatocellular carcinoma are urgently needed. Herein, six novel multifunctional platinum(IV) complexes through linking platinum(II) agents and glycyrrhetinic acid (GA) were designed and synthesized. Among them, complex 20 showed superior antitumor activity against tested cancer cells including cisplatin resistance cells than cisplatin and simultaneously displayed good liver-targeting ability. Moreover, complex 20 can significantly cause DNA damage and mitochondrial dysfunction, promote reactive oxygen species generation, activate endoplasmic reticulum stress, and eventually induce apoptosis. Additionally, complex 20 can effectively inhibit cell migration and invasion and trigger autophagy and ferroptosis in HepG-2 cells. More importantly, complex 20 demonstrated stronger tumor inhibition ability than cisplatin or the combo of cisplatin/GA with almost no systemic toxicity in HepG-2 or A549 xenograft models. Collectively, complex 20 could be developed as a potential anti-HCC agent for cancer treatment.

Tumor recurrence and drug resistance are responsible for poor prognosis in colorectal cancer (CRC). DNA mismatch repair (MMR) deficiency or elevated interleukin-8 (IL-8) levels are characteristics of CRCs, which have been independently correlated with treatment resistance to common therapies. We recently demonstrated significantly impaired therapeutical response and increased IL-8 release of CRC cell lines with reduced expression of MMR protein MLH1 as well as cytoskeletal non-erythrocytic spectrin alpha II (SPTAN1). In the present study, decreased intratumoral MLH1 and SPTAN1 expression in CRCs could be significantly correlated with enhanced serum IL-8. Furthermore, using stably reduced SPTAN1-expressing SW480, SW620 or HT-29 cell lines, the RAS - mediated RAF / MEK / ERK pathway was analyzed. Here, a close connection between low SPTAN1 expression, increased IL-8 secretion, enhanced extracellular-signal-regulated kinase (ERK) phosphorylation and a mesenchymal phenotype were detected. The inhibition of ERK by U0126 led to a significant reduction in IL-8 secretion, and the combination therapy of U0126 with FOLFOX optimizes the response of corresponding cancer cell lines. Therefore, we hypothesize that the combination therapy of FOLFOX and U0126 may have great potential to improve drug efficacy on this subgroup of CRCs, showing decreased MLH1 and SPTAN1 accompanied with high serum IL-8 in affected patients.

FOLFOXIRI chemotherapy is a first-line therapy for advanced or metastatic colorectal cancer (CRC), yet its therapeutic efficacy remains limited. Immunostimulatory therapies like oncolytic viruses can complement chemotherapies by fostering the infiltration of the tumor by immune cells and enhancing drug cytotoxicity. In this study, we explored the effect of combining the FOLFOXIRI chemotherapeutic agents with the oncolytic coxsackievirus B3 (CVB3) PD-H in the CRC cell line Colo320. Additionally, we examined the impact of the drugs on the expression of microRNAs (miRs), which could be used to increase the safety of oncolytic CVB3 containing corresponding miR target sites (miR-TS). The measurement of cytotoxic activity using the Chou-Talalay combination index approach revealed that PD-H synergistically enhanced the cytotoxic activity of oxaliplatin (OX), 5-fluorouracil (5-FU) and SN-38. PD-H replication was not affected by OX and SN-38 but inhibited by high concentrations of 5-FU. MiR expression levels were not or only slightly elevated by the drugs or with drug/PD-H combinations on Colo320 cells. Moreover, the drug treatment did not increase the mutation rate of the miR-TS inserted into the PD-H genome. The results demonstrate that the combination of FOLFOXIRI drugs and PD-H may be a promising approach to enhance the therapeutic effect of FOLFOXIRI therapy in CRC.

YAP and TAZ, the Hippo pathway terminal transcriptional activators, are frequently upregulated in cancers. In tumor cells, they have been mainly associated with increased tumorigenesis controlling different aspects from cell cycle regulation, stemness, or resistance to chemotherapies. In fewer cases, they have also been shown to oppose cancer progression, including by promoting cell death through the action of the p73/YAP transcriptional complex, in particular after chemotherapeutic drug exposure. Using HCT116 cells, we show here that oxaliplatin treatment led to core Hippo pathway down-regulation and nuclear accumulation of TAZ. We further show that TAZ was required for the increased sensitivity of HCT116 cells to oxaliplatin, an effect that appeared independent of p73, but which required the nuclear relocalization of TAZ. Accordingly, Verteporfin and CA3, two drugs affecting the activity of YAP and TAZ, showed antagonistic effects with oxaliplatin in co-treatments. Importantly, using several colorectal cell lines, we show that the sensitizing action of TAZ to oxaliplatin is dependent on the p53 status of the cells. Our results support thus an early action of TAZ to sensitize cells to oxaliplatin, consistent with a model in which nuclear TAZ in the context of DNA damage and p53 activity pushes cells towards apoptosis., (© 2024. The Author(s).)

A brand-new enhanced starvation is put forward to trigger sensitized chemotherapy: blocking tumor-relation blood vessel formation and accelerating nutrient degradation and efflux. Following this concept, two cisplatin-like gemfibrozil-derived Pt(IV) prodrugs, GP and GPG, are synthesized. GP and GPG had nanomolar IC 50 against A2780 cells and higher selectivity against normal cells than cisplatin. Bioactivity results confirmed that GP and GPG highly accumulated in cells and induced DNA damage, G2-phase arrest, and p53 expression. Besides, they could increase ROS and MDA levels and reduce mitochondrial membrane potential and Bcl-2 expression to promote cell apoptosis. In vivo, GP showed superior antitumor activity in A2780 tumor-bearing mice with no observable tissue damage. Mechanistic studies suggested that highly selective chemotherapy could be due to the new enhanced starvation effect: blocking vasculature formation via inhibiting the CYP2C8/EETs pathway and VEGFR2, NF-κB, and COX-2 expression and cholesterol efflux and degradation acceleration via increasing ABCA1 and PPARα.

One of the key strategies in chemotherapy involves crosslinking the DNA strands of cancer cells to impede their replication, with platinum (Pt) coordination compounds being a prominent class and cisplatin being its major representative. Steroidal ligands tethered to DNA interactive Pt core act as drug carriers for targeted therapy. While crosslinking of nuclear or mitochondrial DNA strands using coordination complexes has been studied for years, there remains a lack of comprehensive reviews addressing the advancements made in steroidal-Pt derivatives. This review specifically focuses on advancements made in steroid-tethered structural derivatives of Pt(II) or prodrug Pt(IV) for targeted chemotherapy, synthesized between 2000 and 2023. This period was deliberately chosen due to the widespread use of computational techniques for more accurate structure-based drug-design in last two decades. This review discusses the strategy behind tethering steroidal ligands such as testosterone, estrogen, bile acids, and cholesterol to the central DNA interactive Pt core through specific linker groups. The steroidal ligands function as drug delivery vehicles of DNA interactive Pt core and bind with their respective target receptors or proteins that are often overexpressed in cancer cells, thus enabling targeted delivery of Pt moiety to interact with DNA. We discussed structural features such as the location of the linker group on the steroid, the mono, bi, and tridentate configuration of the chelating arm in coordination with Pt, and the rigidity and flexibility of the linker group. The comparative in vitro, in vivo activities, and relative binding affinities of the designed compounds against standard Pt drugs are also discussed. We also provided a critique of observed trends and shortcomings. Our review will provide insights into future molecular designing of targeted DNA crosslinkers and their structural optimization to achieve desired drug properties. From this analysis, we proposed further research directions leading to the future of targeted chemotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Our previous work indicated that the addition of lobaplatin to combined therapy with taxane and anthracycline can improve the pathological complete response rate of neoadjuvant therapy for triple-negative breast cancer (TNBC) and lengthen long-term survival significantly, but the therapeutic markers of this regimen are unclear., Methods: Eighty-three patients who met the inclusion criteria were included in this post hoc analysis. We analyzed the association between platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) before neoadjuvant chemotherapy with the efficacy and prognosis after treatment with docetaxel, epirubicin, and lobaplatin neoadjuvant chemotherapy regimen. χ2 test and Cox regression were used to analyze the association between PLR and NLR with total pathologic complete response (tpCR), as well as the association between PLR and NLR with event-free survival (EFS) and overall survival (OS), respectively., Results: The tpCR rate in the PLR- group was 49.0% (25/51), which was significantly higher than that in the PLR+ group (25.0% [8/32], P = .032). The tpCR rate in the NLR- group was 49.1% (26/53), which was significantly higher than that in the NLR+ group (23.3% [7/30], P = .024). The tpCR rate of the PLR-NLR- (PLR- and NLR-) group was 53.7% (22/41), which was significantly higher than that of the PLR+/NLR+ (PLR+ or/and NLR+) group (26.1% [11/42]; P = .012). EFS and OS in the NLR+ group were significantly shorter than those in the NLR- group (P = .028 for EFS; P = .047 for OS). Patients in the PLR-NLR- group had a longer EFS than those in the PLR+/NLR+ group (P = .002)., Conclusion: PLR and NLR could be used to predict the efficacy of neoadjuvant therapy with the taxane, anthracycline, and lobaplatin regimen for patients with TNBC, as patients who had lower PLR and NLR values had a higher tpCR rate and a better long-term prognosis., (© The Author(s) 2024. Published by Oxford University Press.)

Drug resistance significantly hampers the clinical application of existing platinum-based anticancer drugs. New platinum medications that possess distinct mechanisms of action are highly desired for the treatment of Pt-resistant cancers. Herein, a nanoscale trans-platinum(II)-based supramolecular coordination self-assembly (Pt-TCPP-BA) is prepared via using trans-[PtCl 2 (pyridine)(NH 3 )] (transpyroplatin), tetracarboxylporphyrin (TCPP), and benzoic acid (BA) as building blocks to combat drug resistance in platinum-based chemotherapy. Mechanistic studies indicate that Pt-TCPP-BA shows a hydrogen-peroxide-responsive dissociation behavior along with the generation of bioactive trans-Pt(II) and TCPP-Pt species. Different from cisplatin, these degradation products interact with DNA via interstrand cross-links and small groove binding, and induce significant upregulation of cell-death-related proteins such as p53, cleaved caspase 3, p21, and phosphorylated H2A histone family member X in cisplatin-resistant cancer cells. As a result, Pt-TCPP-BA exhibits potent killing effects against Pt-resistant tumors both in vitro and in vivo. Overall, this work not only provides a new platinum drug for combating drug-resistant cancer but also offers a new paradigm for the development of platinum-based supramolecular anticancer drugs., (© 2024 Wiley‐VCH GmbH.)

Although cisplatin has been widely used for clinical purposes, its application is limited due to its obvious side effects. To mitigate the defects of cisplatin, here, six "multitarget prodrugs" were synthesized by linking cisplatin and NF-κB inhibitors. Notably, complex 9 demonstrated a 63-fold enhancement in the activity against A549/CDDP cells with lower toxicity toward normal LO2 cells compared to cisplatin. Additionally, complex 9 could effectively cause DNA damage, induce mitochondrial dysfunction, generate reactive oxygen species, and induce cell apoptosis through the mitochondrial pathway and ER stress. Remarkably, complex 9 effectively inhibited the NF-κB/MAPK signaling pathway and disrupted the PI3K/AKT signaling transduction. Importantly, complex 9 showed superior in vivo antitumor efficiency compared to cisplatin or the combination of cisplatin/ 4 , without obvious systemic toxicity in A549 or A549/CDDP xenograft models. Our results demonstrated that the dual-acting mechanism endowed the complexes with high efficiency and low toxicity, which may represent an efficient strategy for cancer therapy.

We report two novel prodrug Pt(IV) complexes with bis-organosilane ligands in axial positions: cis -dichloro(diamine)- trans -[3-(triethoxysilyl)propylcarbamate]platinum(IV) (Pt(IV)-biSi-1) and cis -dichloro(diisopropylamine)- trans -[3-(triethoxysilyl) propyl carbamate]platinum(IV) (Pt(IV)-biSi-2). Pt(IV)-biSi-2 demonstrated enhanced in vitro cytotoxicity against colon cancer cells (HCT 116 and HT-29) compared with cisplatin and Pt(IV)-biSi-1. Notably, Pt(IV)-biSi-2 exhibited higher cytotoxicity toward cancer cells and lower toxicity on nontumorigenic intestinal cells (HIEC6). In preclinical mouse models of colorectal cancer, Pt(IV)-biSi-2 outperformed cisplatin in reducing tumor growth at lower concentrations, with reduced side effects. Mechanistically, Pt(IV)-biSi-2 induced permanent DNA damage independent of p53 levels. DNA damage such as double-strand breaks marked by histone gH2Ax was permanent after treatment with Pt(IV)-biSi-2, in contrast to cisplatin's transient effects. Pt(IV)-biSi-2's faster reduction to Pt(II) species upon exposure to biological reductants supports its superior biological response. These findings unveil a novel strategy for designing Pt(IV) anticancer prodrugs with enhanced activity and specificity, offering therapeutic opportunities beyond conventional Pt drugs.