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Epidermal growth factor receptor (EGFR) is a validated target for non-small-cell lung cancer (NSCLC). However, the treatment for EGFR-C797S mutation induced by third-generation EGFR inhibitors remains a concern. Therefore, the development of the fourth-generation EGFR inhibitors to overcome the EGFR-C797S mutation has great potential for clinical treatment. In this article, we designed and synthesized a series of diphenyl ether substituted quinazolin-4-amine derivatives that simultaneously occupy the ATP binding pocket and the allosteric site of EGFR. Among the newly synthesized compounds, 9d displayed excellent kinase activity against EGFR L858R/T790M/C797S with an IC 50 value of 0.005 μM, and exhibited anti-proliferation activity in BaF3-EGFR L858R/T790M/C797S cells with the IC 50 value of 0.865 μM. Furthermore, 9d could suppress phosphorylation of EGFR and induce cell apoptosis and cycle arrest at G2 phase in a dose-dependent manner in BaF3-EGFR L858R/T790M/C797S cells. More importantly, 9d displayed significant antitumor effects in BaF3-EGFR L858R/T790M/C797S xenograft mouse model (30 mg/kg, TGI = 71.14 %). All the results indicated compound 9d might be a novel fourth-generation EGFR inhibitor for further development in overcoming the EGFR-C797S resistance mutation., 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.)

Hepatocellular carcinoma (HCC) is considered as one of the leading causes of death in liver disease patients. Several signal transduction pathways are involved in HCC pathogenesis. Multikinase inhibitors (MKIs) show beneficial effects for HCC and the FDA approved a few MKIs including sorafenib, lenvatinib for HCC treatments. Here, a novel series of phenylacetamide derivatives were designed, synthesized and evaluated as multikinase inhibitors. Several compounds showed nanomolar IC 50 values against FLT1, FLT3, FLT4, KDR, PDGFRα, PDGFRβ. The compounds were tested against human hepatocellular carcinoma (HCC), human colon adenocarcinoma and human gastric carcinoma cell lines. With favorable pharmacokinetics profiles, compound 12 and compound 14 were selected for in vivo efficacy studies in Hep3B mice models and demonstrated efficacious than sorafenib., 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.)

Disrupting microtubule dynamics has emerged as a promising strategy for cancer therapy. Novel trimethoxyanilino-substituted pyrimidine and quinazoline derivatives were designed and synthesized to serve as potent microtubule-inhibiting agents with anti-proliferative activity. Compound 2k demonstrates high efficacy against B16-F10 cancer cells at low nanomolar concentrations, with an IC 50 of 0.098 ± 0.006 μM, which is comparable to colchicine. Mechanistic studies have revealed that 2k has the ability to inhibit microtubule protein polymerization in vitro, resulting in cell cycle arrest and apoptosis. Furthermore, 2k inhibits tumor cell migration and exhibits significant anti-tumor efficacy in a melanoma tumor model without causing obvious toxicity. In summary, the pyrimidine derivative 2k exhibits excellent anticancer activity and provides a new scaffold for the development of novel microtubule inhibitors, which deserves further in-depth research., 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.)

Pancreatic and colon cancer are malignant tumors of the digestive system that currently lack effective treatments. In cancer cells, a high level of glutathione (GSH) is indispensable to scavenge excessive reactive oxygen species (ROS) and detoxify xenobiotics, which make it a potential target for cancer therapy. GSH depletion has been proved to improve the therapeutic efficacy of photodynamic therapy. Here, we reported that naked mesoporous rhodium nanospheres (Rh MNs), prepared by soft template redox method, can act as GSH depletion agent and photothermal conversion agent to achieve synergistic therapy respectively. Different from conventional nanoagents, Rh MNs with the characteristics of easy synthesis, simple structure and multiple functions can decrease the GSH level in tumor and depict excellent photothermal ability with a high photothermal conversion efficiency (PTCE) up to 39%. Notably, multiple anti-tumor mechanisms in CT26 and BxPC-3 tumor models, include inhibited anti-apoptosis, DNA replication repair, and GSH synthesis are revealed, and the pancreatic tumor cure rate of the cooperative treatment group is 80%. Collectively, we developed Rh MNs to combine GSH depletion with photothermal therapy for cancer treatment., 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.)

The deficiency in available targeted agents and frequency of chemoresistance are primary challenges in clinical management of triple-negative breast cancer (TNBC). The aberrant expression of USP21 and JAK2 represents a characterized mechanism of TNBC progression and resistance to paclitaxel (PTX). Despite its clear that high expression of USP21-mediated de-ubiquitination leads to increased levels of JAK2 protein, we lack regulator molecules to dissect the mechanisms that the interaction between USP21 and JAK2 contributes to the phenotype and resistance of TNBC. Here, we report a USP21/JAK2/STAT3 axis-targeting regulator 13c featuring a N-anthraniloyl tryptamine scaffold that showed excellent anti-TNBC potency and promising safety profile. Importantly, the therapeutic potential of using 13c in combination with PTX in PTX-resistant TNBC was demonstrated. This study showcases N-anthraniloyl tryptamine derivatives as a novel anti-TNBC chemotype with a pharmacological mode of action targeting the USP21/JAK2/STAT3 axis and provides a potential therapeutic target for the treatment of TNBC., 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.)

Bladder cancer (BC) is the most common malignant tumor in urinary system. Although chemotherapy is one of the most important adjuvant treatments for BC, drug resistance, non-specific toxicity and severe side effects are the major obstacles to BC chemotherapy. Natural products have always been a leading resource of antitumor drug discovery, with the advantages of excellent effectiveness, low toxicity, multi-targeting potency and easy availability. In this study, we evaluated the potential anti-tumor effect of securinine (SEC), a natural alkaloid from Securinega suffruticosa, on BC cells in vitro and in vivo, and delineated the underlying mechanism. We found that SEC inhibited the proliferation, migration and invasion, induced the apoptosis of BC cells in vitro, and retarded the xenograft tumor growth of BC cell in vivo. Notably, SEC had a promising safety profile because it presented no or low toxicity on normal cells and mice. Mechanistically, SEC inactivated Wnt/β-catenin signaling pathway while activated p38 and JNK signaling pathway. Moreover, β-catenin overexpression, the p38 inhibitor SB203580 and the JNK inhibitor SP600125 both mitigated the inhibitory effect of SEC on BC cells. Furthermore, we demonstrated a synergistic inhibitory effect of SEC and gemcitabine (GEM) on BC cells in vitro and in vivo. Taken together, our findings suggest that SEC may exert anti-BC cell effect at least through the activation of p38 and JNK signaling pathways, and the inhibition of Wnt/β-catenin signaling pathway. More meaningfully, the findings indicate that GEM-induced BC cell killing can be enhanced by combining with SEC., 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.)

The establishment of structure activity relationship (SAR) for rakicidin derivatives is pretty vital to develop rakicidins as a new type of anti-cancer agents. Herein, two novel rakicidin derivatives, compounds B1-1 ( 1 ) and B1-2 ( 2 ), a cyclic depsipeptide and a chain lipopeptide, respectively, were isolated from culture broth of Micromonospora chalcea FIM-R160609, and their structures were elucidated clearly by extensive NMR and HR-ESI-MS analyses. Following, their cytotoxic activities were evaluated against HCT-8 and PANC-1 human cancer cell lines under hypoxic and normoxic conditions. Their activities were significantly decreased when compared with that of rakicidin B1. These results demonstrated that the double bond located on the position 9 and 10 of conjugated diene unit and cycle-type structure plays an important role in keeping the biological activity of rakicidins. Furthermore, the positive effect of double bond and cycle form on the anti-bacterial activities were also confirmed by testing their inhibitory activities against gram positive bacteria. This work will definitely diversify the SAR of rakicidins and provide the guidance for the design of new potent rakicidin analogues.

Four Ru(II)-centered isomeric complexes [RuCl(5cqn)(Val)(NO)] (1-4) were synthesized with 5cqn (5-chloro-8-hydroxyquinoline) and chiral Val (Val = L- or D-valine) as co-ligand, and their structures were confirmed using the X-ray diffraction method. The cytotoxicity and photodynamic activity of the isomeric complexes and their human serum albumin (HSA) complex adducts were evaluated. Both the isomeric complexes and their HSA complex adducts significantly affected HeLa cell proliferation, with an IC50 value in the range of 0.3-0.5 μM. The photo-controlled release of nitric oxide (NO) in solution was confirmed using time-resolved Fourier transform infrared and electron paramagnetic resonance spectroscopy techniques. Furthermore, photoinduced NO release in living cells was observed using a selective fluorescent probe for NO. Moreover, the binding constants (Kb) of the complexes with HSA were calculated to be 0.17-1.98 × 104 M-1 and the average number of binding sites (n) was found to be close to 1, it can serve as a crucial carrier for delivering metal complexes. The crystal structure of the HSA complex adduct revealed that one [RuCl(H2O)(NO)(Val)]+ molecule binds to a pocket in domain I. This study provides insight into possible mechanism of metabolism and potential applications for nitrosylruthenium complexes., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Mammary carcinoma, a pervasive and potentially lethal affliction, is conjectured to be profoundly influenced by physical exercise, both in prophylaxis and therapeutic contexts. This study endeavors to explore the repercussions of exercise training on the progression of mammary carcinoma, particularly the mechanisms by which the amalgamation of an exercise regimen and doxorubicin induces tumor cell apoptosis., Methods: Female BALB/c mice were categorized into four distinct groups: A sedentary group (SED), an exercise group (Ex), a doxorubicin group (Dox, 5 mg/kg), and a combined treatment group (Dox + Ex). The exercise training lasted for 21 days and included aerobic rotarod exercise and resistance training. The impact of exercise training on tumor growth, immune cell proportions, inflammatory factor levels, and cell apoptosis pathway was assessed., Results: Exercise training significantly curtailed tumor growth in a mouse model of breast cancer. Both the Ex and Dox groups exhibited significant reductions in tumor volume and weight (p < 0.01) in comparison to the SED group, while the Dox + Ex group had a significantly lower tumor volume and weight than the Dox group (p < 0.01). Exercise training also significantly increased the proportion of NK and T cells in various parts of the body and tumor tissue, while decreasing tumor blood vessels density. Exercise training also increased IL-6 and IL-15 levels in the blood and altered the expression of apoptosis-related proteins in tumor tissue, with the combined treatment group showing even more significant changes., Conclusions: Physical training improves the effectiveness of doxorubicin in treating breast cancer by activating cytotoxic immune cells, releasing tumor suppressor factors, and initiating mt-apoptosis, all while mitigating the adverse effects of chemotherapy., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Cancer is an important factor affecting the quality of human life as well as causing death. Tumor ablation therapy is a minimally invasive local treatment modality with unique advantages in treating tumors that are difficult to remove surgically. However, due to its physical and chemical characteristics and the limitation of equipment technology, ablation therapy cannot completely kill all tumor tissues and cells at one time; moreover, it inevitably damages some normal tissues in the surrounding area during the ablation process. Therefore, this technology cannot be the first-line treatment for tumors at present. Metal nanoparticles themselves have good thermal and electrical conductivity and unique optical and magnetic properties. The combination of metal nanoparticles with tumor ablation technology, on the one hand, can enhance the killing and inhibiting effect of ablation technology on tumors by expanding the ablation range; on the other hand, the ablation technology changes the physicochemical microenvironment such as temperature, electric field, optics, oxygen content and pH in tumor tissues. It helps to stimulate the degree of local drug release of nanoparticles and increase the local content of anti-tumor drugs, thus forming a synergistic therapeutic effect with tumor ablation. Recent studies have found that some specific ablation methods will stimulate the body's immune response while physically killing tumor tissues, generating a large number of immune cells to cause secondary killing of tumor tissues and cells, and with the assistance of metal nanoparticles loaded with immune drugs, the effect of this anti-tumor immunotherapy can be further enhanced. Therefore, the combination of metal nanoparticles and ablative therapy has broad research potential. This review covers common metallic nanoparticles used for ablative therapy and discusses in detail their characteristics, mechanisms of action, potential challenges, and prospects in the field of ablation.

Human epidermal growth factor receptor 2 (HER2) is considered an ideal antibody-drug conjugate (ADC) target because the gene is overexpressed in many tumors compared to normal tissues. Multiple anti-HER2 ADCs conjugated with different toxic payloads bring benefits to patients with high HER2 expression. However, HER2-targeted ADC technology needs further optimization to improve its effect for the treatment of patients with low HER2 expression. We hypothesized that bispecific antibody-drug conjugate (bsADC) targeting HER2 and Sortilin-1 (SORT1) would overcome this limitation. SORT1 is a suitable target for pairing with HER2 to generate a bispecific antibody (BsAb) since the gene is co-expressed with HER2 in tumors and possesses rapid internalization. We developed a BsAb (bsSORT1×HER2) that exhibited strong binding and internalization activity on HER2-low-expression tumor cells and facilitated higher HER2 degradation. The bsSORT1×HER2 was further conjugated with DXd to generate a bsADC (bsSORT1×HER2-DXd) that showed strong cytotoxicity on HER2-low-expression tumor cells and antitumor efficacy in an MDA-MB-231 xenograft mice model. These results demonstrated that employment of a SORT1×HER2-targeted bsADC may be promising to improve the antitumor efficacy of HER2-targeted ADC for the treatment of tumors with low HER2 expression.

Irinotecan (Ir) is commonly employed as a first-line chemotherapeutic treatment for colorectal cancer (CRC). However, tremendous impediments remain to be addressed to surmount drug resistance and ameliorate adverse events. Poly-ADP-Ribose Polymerase (PARP) participates in the maintenance of genome stability and the repair of DNA damage, thus playing a critical role in chemotherapy resistance. In this work, we introduce a novel curative strategy that utilizes nanoparticles (NPs) prepared by dynamic supramolecular co-assembly of Ir and a PARP inhibitor (PARPi) niraparib (Nir) through π-π stacking and hydrogen bond interactions. The Ir and Nir self-assembled Nano-Twin-Drug of (Nir-Ir NPs) could enhance the therapeutic effect on CRC by synergistically inhibiting the DNA damage repair pathway and activating the tumor cell apoptosis process without obvious toxicity. In addition, the Nir-Ir NPs could effectively reverse irinotecan-resistance by inhibiting the expression of multiple resistance protein-1 (MRP-1). Overall, our study underscores the distinctive advantages and potential of Nir-Ir NPs as a complementary strategy to chemotherapy by simultaneously overcoming the Ir resistance and improving the anti-tumor efficacy against CRC., (© 2023. The Author(s).)

Background: Chemotherapy-induced nausea and vomiting (CINV) is one of the most distressing side effects associated with deterioration in the quality of life. This study aimed to assess the clinical value of Huoxiang Zhengqi (HXZQ) oral liquid, a Chinese patent medicine, in combination with 5-HT3 receptor antagonists (RAs) and dexamethasone, in preventing CINV in patients receiving multiday cisplatin-based chemotherapy. Methods: In this multicenter, exploratory randomized clinical trial, the authors compared the efficacy of HXZQ oral liquid against a control group receiving a placebo, in combination with 5-HT3 RAs and dexamethasone, in preventing CINV in chemotherapy-naive patients receiving a multiday cisplatin-based regimen between January 2021 and September 2021. The primary endpoint was the complete response (CR) rate. The secondary endpoints included days with no CINV, the incidence of CINV, and life function. Results: Sixty patients were randomized into two groups and included in the study. The CR rate was significantly improved by HXZQ oral liquid in acute CINV (63.33% vs. 33.33%, p  = 0.020) and CINV beyond the risk phase (96.67% vs. 46.67%, p  = 0.000). The number of days with no CINV was significantly more in the HXZQ group compared with the control group in the overall phase (18.10 ± 3.64 vs. 12.13 ± 7.63, p  = 0.002). Significantly higher Functional Living Index-Emesis total and domain scores were observed in the HXZQ group. Conclusions: HXZQ oral liquid combined with 5-HT3 RAs and dexamethasone is a feasible and safe approach to prevent CINV in patients receiving multiday cisplatin-based chemotherapy who cannot use neurokinin 1 RAs. Clinical Trial Registration: ChiCTR2000040123.

Background: The evidence of transcatheter arterial chemoembolization (TACE) plus tyrosine kinase inhibitor and immune checkpoint inhibitor in unresectable hepatocellular carcinoma (HCC) was limited. This study aimed to evaluate the role of TACE plus apatinib (TACE + A) and TACE combined with apatinib plus camrelizumab (TACE + AC) in patients with unresectable HCC., Methods: This study retrospectively reviewed patients with unresectable HCC who received TACE + A or TACE + AC in 20 centers of China from January 1, 2019 to June 31, 2021. Propensity score matching (PSM) at 1:1 was performed to reduce bias. Treatment-related adverse events (TRAEs), overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were collected., Results: A total of 960 eligible patients with HCC were included in the final analysis. After PSM, there were 449 patients in each group, and the baseline characteristics were balanced between two groups. At data cutoff, the median follow-up time was 16.3 (range: 11.9-21.4) months. After PSM, the TACE + AC group showed longer median OS (24.5 vs 18.0 months, p < 0.001) and PFS (10.8 vs 7.7 months, p < 0.001) than the TACE + A group; the ORR (49.9% vs 42.5%, p = 0.002) and DCR (88.4% vs 84.0%, p = 0.003) of the TACE + AC group were also higher than those in the TACE + A group. Fever, pain, hypertension and hand-foot syndrome were the more common TRAEs in two groups., Conclusions: Both TACE plus apatinib and TACE combined with apatinib plus camrelizumab were feasible in patients with unresectable HCC, with manageable safety profiles. Moreover, TACE combined with apatinib plus camrelizumab showed additional benefit., (© 2023. The Author(s).)

To prevent local tumor recurrence caused by possible residual cancer cells after surgery, avoid toxicity of systemic chemotherapy and protect the fragile immune system of postsurgical patients, an increasing amount of attention has been paid to local anti-cancer drug delivery systems. In this paper, golden buckwheat was first applied to prevent post-operative tumor recurrence, which is a Chinese herb and possesses anti-tumor activity. Golden buckwheat extract-loaded gellan gum injectable hydrogels were fabricated via Ca 2+ crosslinking for localized chemotherapy. Blank and/or drug-loaded hydrogels were characterized via FT-IR, TG, SEM, density functional theory, drug release and rheology studies to explore the interaction among gellan gum, Ca 2+ and golden buckwheat extract (GBE). Blank hydrogels were non-toxic to NIH3T3 cells. Of significance, GBE and GBE-loaded hydrogel inhibited the proliferation of tumor cells (up to 90% inhibition rate in HepG2 cells). In vitro hemolysis assay showed that blank hydrogel and GBE-loaded hydrogel had good blood compatibility. When GBE-loaded hydrogel was applied to the incompletely resected tumor of mice bearing B16 tumor xenografts, it showed inhibition of tumor growth in vivo and induced the apoptosis of tumor cells. Taken together, gellan gum injectable hydrogel containing GBE is a potential local anticancer drug delivery system for the prevention of postsurgical tumor recurrence.

Six new Pd(II), Pt(II) and Ag(I) complexes, (1);{Pd (L 1 )]2C 6 H 4 } 2 Cl 4 } (2); Pt(L 2 )(DMSO)Cl; 3; {PtL 5 ] 2 C 6 H 4 } 2 ·PhCOO - ⋅11NO 3 ; 4; {[Pt(L - ; 4; {[Pt(L 4 )] 2 C 6 H 4 }; the binuclear cyclometalated complex the polymer chain (5); {[PtL 5 ]C 6 H 4 }; and the polymeric silver species (6); Zn(L 3 - }; and the polymeric silver species (6); Zn(L 6 ) 2 were synthesized and thoroughly characterized using X-ray diffraction and spectroscopic techniques (L 3 ·CHCl 3 were synthesized and thoroughly characterized using X-ray diffraction and spectroscopic techniques (L 1 =(S,S)-1,4-i-PrOx] 2 C 6 H 4 , L 2 Cl 4 );L 2 =Di(2,2-bis(4R-isopropyl-4,5-dihydro-oxazol-2-yl)acetonitrile) zinc (II) (B R1 ); L 3 = 1,4-bis(4R-benzyl-4,5-dihydro-oxazol-2-yl)benzene，L R2 =1,4-bis(4R-benzyl-4,5-dihydro-oxazol-2-yl)-benzene，L 4 = 1,4-bis(4R-benzyl-4,5-dihydro-oxazol-2-yl)benzene，L 5 =1,4-bis(4R-benzyl-4,5-dihydro-oxazol-2-yl)-benzene，L 6 =Di(2,2-bis(4S-isopropyl-4,5-dihydrooxazol-2-yl)acetonitrile) zinc (II). Complexes 1-6 showed cytotoxic effects against human tumour cell lines, including a multidrug-resistant subline. Oxazoline and Pd complex 1 induced apoptosis in A549 cells. DFT calculations were also performed to exhibit the excellent bioactivity of complex 1 against A549, MDA-MB-231, and KB cells. Complex 1, with the best docking score and a stable interaction network within the binding site of the G-quadruplex, could stably interact with the G-quadruplex. Additionally, complex 1 was further used in the animal experiment of human lung adenocarcinoma cells in nude mice. By comparing with the model control group, the tumour volume, relative tumour volume and relative tumour proliferation rate T/C decreased significantly in the cisplatin group and compound 1 (complex 1) group., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: This study sought to explore and summarize the global state of acupuncture clinical trials enrolling cancer patients included in international registries to date., Methods: All relevant trials evaluating acupuncture-related interventions for the treatment of cancer that were registered in 16 trial registries from January 1, 2001, through December 31, 2020, were identified. Subsequent publications related to these trials were additionally retrieved from the PubMed, Cochrane Library, Embase, CNKI (China National Knowledge Infrastructure), VIP (China Science and Technology Journal Database), and Wanfang databases. We compared information included in these registries regarding completed trials with any associated publications, with a focus on study design, sample size, and selective reporting, based on the registered protocol., Results: In total, 222 eligible trials across 19 countries were identified. These trials included 17 specific cancer types and 32 symptoms. The five most common cancer types were breast cancer, head and neck cancer, colorectal cancer, lung cancer, and gastric cancer, accounting for almost half of all registered trials (48.2%). The top five symptoms included in these trials were chemotherapy-induced peripheral neuropathy (CIPN), cancer-related pain, cancer-related fatigue, chemotherapy-induced nausea and vomiting (CINV), and gastrointestinal dysfunction. The overall rate of article publication was low, with publications being associated with just 33.3% of these registered trials., Conclusions: This review is the first snapshot of the landscape of acupuncture clinical trials registered in international trial registries, providing a methodological basis for the management of common treatment- and disease-related side effects among cancer patients undergoing acupuncture and offering useful information that will guide future acupuncture-focused research., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Phenylahistin is a naturally occurring marine product with a diketopiperazine structure that can bind to the colchicine site of microtubulin as a possible anticancer agent. To develop more potent microtubule inhibitors, novel phenylahistin derivatives were designed and synthesized based on the co-crystal complexes of phenylahistin derivatives and microtubulin. We established a focused library of imidazole-type molecules for the introduction of different groups to the C-ring and A-ring of phenylahistin. Structure-activity relationship studies indicated that appropriate hydrocarbon substituents and unsaturated alkenyl substituents at the 1-position of the imidazole group are important for improving the activity of such compounds. In addition, this study found that propylamine groups could maintain the activity of these compounds, as exemplified by compound 16d (IC 50 = 5.38 nM, NCI-H460). Compound 15p (IC 50 = 1.03 nM, NCI-H460) with an allyl group exhibited potent cytotoxic activity at the nanomolar level against human lung cancer cell lines. Immunofluorescence assay indicated that compound 15p could efficiently inhibited microtubule polymerization and induced a high expression of caspase-3. 15p also displayed good pharmacokinetic characteristics in vitro. Additionally, the growth of H22 transplanted tumors was significantly inhibited in BALB/c mice when 15p alone was administered at 4 mg/kg, and the tumor inhibition rate was as much as 65%. Importantly, the continuous administration of 15p resulted in a lower toxicity than that of docetaxel (10 mg/kg) and cyclophosphamide (20 mg/kg). Overall, the novel allyl-imidazole-diketopiperazine-type derivatives could be considered safe and effective potential agents for cancer treatment.

Background: An over-expression of the epidermal growth factor receptor (EGFR) has been observed in colorectal cancer and is associated with aggressive disease and poor prognosis. SCT200 is a newly developed recombinant, fully humanized, anti-EGFR monoclonal antibody. This study aimed to evaluate its safety, tolerability, pharmacokinetics (PK), and efficacy in patients with wild-type KRAS/NRAS/BRAF metastatic colorectal cancer (mCRC).  METHODS: This phase I study comprising dose-escalation phase and dose-expansion phase. SCT200 was administrated intravenously to groups of three to six patients. An every 3-week dosing cycle (0.5-15.0 mg/kg) and multiple dosing schedule were evaluated. Blood samples were collected at preset intervals for PK assessment, radiological imaging was used for efficacy assessment, and continuous safety monitoring was performed in each group during the study.  RESULTS: From December 16, 2014 to December 31, 2018, fifty-six patients with wild-type KRAS/NRAS/BRAF mCRC receiving ≥ 1 dose of SCT200 were evaluated. Among them, 44.6% (25/56) of the patients failed at least two prior lines of chemotherapy. No dose-limiting toxicities occurred in any group. All of the patients experienced treatment-emergent adverse events (TEAEs). 96.4% (54/56) of patients experienced treatment-related adverse events (TRAEs), and 26.8% (15/56) of patients with Grade ≥ 3 TRAEs. No serious TRAEs were observed. The most common TRAEs were dermotoxicity and hypomagnesemia. PK analysis showed non-linear PK in the range of 0.5 - 8.0 mg/kg of single dose SCT200, the clearance decreased, and the elimination half-life (T 1/2 ) prolonged following dose increase. In the multiple-dose period, the clearance decreased, peak concentration increased, and T 1/2 prolonged during prolonged drug administration, and a steady state was reached after five consecutive dose of 6.0 mg/kg quaque week (QW). The objective response rate (ORR) was 30.4% (17/56, 95% confidence interval [CI], 18.8%-44.1%). The ORR in the dose-expansion group (6.0 mg/kg QW) was 48.0% (12/25, 95% CI, 27.8%-68.7%), the median progression-free survival was 5.2 months (95%CI, 3.6-5.5), and the median overall survival was 20.2 months (95%CI, 12.1-not reached)., Conclusions: SCT200 showed favorable safety, PK profile, and preliminary efficacy for patients with wild-type KRAS/NRAS/BRAF mCRC., Trial Registration: This study was registered with ClinicalTrials.gov ( NCT02211443 )., (© 2022. The Author(s).)

To explore novel topoisomerase inhibitors with high activity and druggability, 3-aryl isoquinoline alkaloids based on the corydamine modification and preliminary SARs of isoquinoline alkaloids in our previous works were re-designed. Currently, the design strategy is mainly revolved around the rigidity and flexibility of the molecular side chain and the molecular size. Consequently, not only the activity and druggability of the compound could be further improved, also the mechanism behind could been discovered. In vitro pharmacological studies, the outstanding nature with the excellent activity and the researchable depth of azepane-substituted compound 7 has been found through the vitro cytotoxicity test (IC 50  = 1.93 μM in HuH7 cells and 2.10 μM in LM9 cells) and topoisomerase test. It was found that compound 7 had dual inhibitory effects on topoisomerase I and II, and its inhibitory activity on topoisomerase II is stronger than the positive drug etoposide. From the perspective of molecular docking, it had been verified that compound 7 could insert between DNA base pairs, which was consistent with the results of the DNA unwinding experiment. And the comet experiment confirmed 7 caused DNA damage. Meanwhile, compound 7 could inhibit cell proliferation, invasion and migration, and induce apoptosis by inhibiting PI3K/Akt/mTOR signaling pathway. Therefore, this study may lay a foundation for the discovery of 3-arylisoquinoline compounds with anti-liver cancer potential., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Docetaxel (DTX) has been widely used for the treatment of many types of cancer. However, DTX is poorly water-soluble and commercial DTX is formulated in non-ionic surfactant polysorbate 80 and ethanol, thereby leading to hypersensitivity and serious side effects. Herein, a polymer dual drug conjugate was synthesized by coupling DTX and docosahexaenoic acid (DHA) with bifunctionalized dextran. The polysaccharide conjugate dextran-DHA-DTX possessed high water solubility and was self-assembled into nanoparticles with a diameter of 98.0 ± 6.4 nm. Pharmacokinetic and biodistribution studies showed that the dextran-DHA-DTX dual drug conjugate not only had significantly prolonged blood circulation but was also selectively accumulated in the tumor with reduced drug distribution in normal tissues. The conjugate exhibited a superior therapeutic effect in both xenograft nude mice models without causing any systemic side effects. Notably, the conjugate nearly eliminated all xenograft tumors in nude mice bearing breast cancer cells MCF-7. This study revealed that the dextran-based dual drug delivery system may provide an effective strategy to selectively deliver DTX to tumor sites.

The prediction of tumor drug sensitivity plays an important role in clinically guiding patients' medication. In this paper, a multi-omics data-based cancer drug sensitivity prediction model was constructed by Stacking ensemble learning method. The data including gene expression, mutation, copy number variation and drug sensitivity value ( IC 50 ) of 198 drugs were downloaded from the GDSC database. Multiple feature selection methods were applied for dimensionality reduction. Six primary learners and one secondary learner were integrated into modeling by Stacking method. The model was validated with 5-fold cross-validation. In the prediction results, 36.4% of drug models' AUCs were greater than 0.9, 49.0% of drug models' AUCs were between 0.8-0.9, and the lowest drug model's AUC was 0.682. The multi-omics model for drug sensitivity prediction based on Stacking method is better than the known single-omics or multi-omics model in terms of accuracy and stability. The model based on multi-omics data is better than the single-omics data in predicting drug sensitivity. Function annotation and enrichment analysis of feature genes revealed the potential resistance mechanism of tumors to sorafenib, providing the model interpretability from a biological perspective, and demonstrated the model's potential applicability in clinical medication guidance.

Background: This study aimed to retrospectively investigate the efficacy and safety of recombinant human endostatin (Rh-endostatin) combined with radiotherapy in advanced non-small-cell lung cancer (NSCLC). Methods: Patients with unresectable stage III and IV NSCLC who treated with radiotherapy were enrolled. Patients who received Rh-endostatin infusion throughout the whole peri-radiotherapy period formed the Endostar group, and those who received no Rh-endostatin infusion were the control group. Results: The median progression-free survival was 8.0 and 4.4 months (hazard ratio: 0.53; 95% CI: 0.32-0.90; p = 0.019) and median overall survival was 40.0 and 13.1 months (hazard ratio: 0.53; 95% CI: 0.28-0.98; p = 0.045) for the Endostar and control groups, respectively. The Endostar group exhibited a numerically lower rate of radiation pneumonitis relapse, radiation pneumonitis death and pulmonary fibrosis. Conclusion: Rh-endostatin infusion throughout the peri-radiotherapy period enhanced radiosensitivity and showed better survival outcomes and a tendency toward fewer radiation-related pulmonary events in patients with NSCLC.

So far, relatively few small molecules have been reported to promote tubulin degradation. Our previous studies have found that compound 2 , a noncovalent colchicine-site ligand, was capable of promoting αβ-tubulin degradation. To further improve its antiproliferative activity, 66 derivatives or analogues of 2 were designed and synthesized based on 2 -tubulin cocrystal structure. Among them, 12b displayed nanomolar potency against a variety of tumor cells, including paclitaxel- and adriamycin-resistant cell lines. 12b binds to the colchicine site and promotes αβ-tubulin degradation in a concentration-dependent manner via the ubiquitin-proteasome pathway. The X-ray crystal structure revealed that 12b binds in a similar manner as 2 , but there is a slight conformation change of the B ring, which resulted in better interaction of 12b with surrounding residues. 12b effectively suppressed tumor growth at an i.v. dose of 40 mg/kg (3 times a week) on both A2780S (paclitaxel-sensitive) and A2780T (paclitaxel-resistant) ovarian xenograft models, with respective TGIs of 92.42 and 79.75% without obvious side effects, supporting its potential utility as a tumor-therapeutic compound.

Bruton's tyrosine kinase (BTK) is an attractive therapeutic target in the treatment of cancer, inflammation, and autoimmune diseases. Covalent and noncovalent BTK inhibitors have been developed, among which covalent BTK inhibitors have shown great clinical efficacy. However, some of them could produce adverse effects, such as diarrhea, rash, and platelet dysfunction, which are associated with the off-target inhibition of ITK and EGFR. In this study, we disclosed a series of pteridine-7(8 H )-one derivatives as potent and selective covalent BTK inhibitors, which were optimized from 3z , an EGFR inhibitor previously reported by our group. Among them, compound 24a exhibited great BTK inhibition activity (IC 50 = 4.0 nM) and high selectivity in both enzymatic (ITK >250-fold, EGFR >2500-fold) and cellular levels (ITK >227-fold, EGFR 27-fold). In U-937 xenograft models, 24a significantly inhibited tumor growth (TGI = 57.85%) at a 50 mg/kg dosage. Accordingly, 24a is a new BTK inhibitor worthy of further development.

Curcumin, a phytochemical derived from the rhizome of turmeric (Curcuma longa L.), has a broad group of substances with antibacterial, anti-inflammatory, anti-oxidant, anticancer activities. The anticancer activity of curcumin and its derivatives are mainly related to its regulation of signal transduction pathways. However, due to the low oral availability of curcumin, fast metabolism and other pharmacokinetic properties limit the application of curcumin in the treatment of cancer. Evidence suggests that curcumin combined with photodynamic therapy can overcome the limitation of curcumin's low bioavailability by acting on apoptosis pathways, such as B-cell lymphoma 2 (Bcl-2) and caspase family, and affecting cell cycle. This paper reviews the structure and pharmacokinetics of curcumin, focusing on the anticancer activity of curcumin combined with photodynamic therapy and the effects on cancer-related signal pathways., (Copyright © 2021. Published by Elsevier Masson SAS.)

Photothermal therapy (PTT) achieves substantive therapeutic progress in certain tumor types without exogenous agents but is hampered by the over-activated inflammatory response or tumor recurrence in some cases. Herein, we technically developed the metal-polyphenolic nanosystem with precise NIR-II fluorescence-imaging guidance for combining hafnium (Hf)-sensitized radiotherapy with PTT to regress tumor growth.

Aim: To elucidate the potential effect of promethazine on colorectal cancer (CRC) cells and the underlying mechanism., Materials and Methods: Targets of the drug promethazine (PMTZ) were identified by DrugBank and comparative toxicogenomic databases (CTD), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed with STRING software. The effects of PMTZ were predicted to be associated with the PI3K/AKT pathway. Cell Counting Kit 8 (CCK-8) assays were used to evaluate the effects of different concentrations of PMTZ on the proliferation of various types of CRC cells. Flow cytometry and Western blotting analyses were used to detect the degree of CRC cell apoptosis and the expression of the apoptosis-related proteins Bcl-2, Bax and caspase-3 after PMTZ treatment. The expression levels of PI3K/AKT pathway-related proteins [PI3K, AKT, phosphorylated (P)-PI3K and p-AKT] in CRC cells treated with PMTZ were analyzed by Western blotting., Results: PMTZ inhibited the proliferation and promoted the apoptosis of CRC cells and suppressed the activation of the PI3K/AKT signaling pathway in a dose-dependent manner., Discussion and Conclusions: PMTZ may suppress the proliferation and induce the apoptosis of CRC cells by inhibiting the PI3K/ AKT signaling pathway. This study reported, for the first time, the function of PMTZ in CRC cells and the underlying mechanism and further confirmed the potential antitumor effects of phenothiazine. The combination of bioinformatics analyses and experiments provides informative evidence for the reuse of drugs and the development of new drugs., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: Although Bruton tyrosine kinase (BTK) inhibitors have demonstrated promising efficacy in patients with Waldenström macroglobulinemia (WM), data in Asian populations are scarce. This trial is the first to investigate the effect of a BTK inhibitor in Chinese patients with relapsed/refractory (R/R) WM., Patients and Methods: Patients with R/R WM with at least one prior regimen were enrolled into this single-arm, multicenter, phase II study (NCT03332173) and received zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. The primary endpoint was major response rate (MRR), as assessed by an independent review committee. Secondary endpoints included progression-free survival, overall response rate, duration of major response, and safety., Results: Forty-four patients were enrolled. After a median follow-up of 33.0 (range, 3.2-36.5) months, MRR in all patients was 69.8%, with very good partial response or better in 32.6% of patients. All mutation groups benefited from zanubrutinib treatment (MRR in patients with MYD88 L265P mutation, 73%; MRR in patients with MYD88 wild type mutation, 50%). A higher response rate was seen in the MYD88 L265P / CXCR4 WT population, compared with the other populations. Median progression-free survival and median duration of major response were not reached. The most frequently reported grade ≥3 treatment-emergent adverse events (AEs) were neutrophil count decreased (31.8%), and platelet count decreased and pneumonia (20.5% each). No case of atrial fibrillation/flutter occurred., Conclusions: Zanubrutinib achieved a high rate of response that was durable and deep in patients with R/R WM across all subgroups, and potentially confers a positive benefit-risk profile for WM., (©2021 The Authors; Published by the American Association for Cancer Research.)

Proteolysis targeting chimeras (PROTACs) represent a new class of promising therapeutic modalities. PROTACs hijack E3 ligases and the ubiquitin-proteasome system (UPS), leading to selective degradation of the target proteins. However, only a very limited number of E3 ligases have been leveraged to generate effective PROTACs. Herein, we report that the KEAP1 E3 ligase can be harnessed for targeted protein degradation utilizing a highly selective, noncovalent small-molecule KEAP1 binder. We generated a proof-of-concept PROTAC, MS83, by linking the KEAP1 ligand to a BRD4/3/2 binder. MS83 effectively reduces protein levels of BRD4 and BRD3, but not BRD2, in cells in a concentration-, time-, KEAP1- and UPS-dependent manner. Interestingly, MS83 degrades BRD4/3 more durably than the CRBN-recruiting PROTAC dBET1 in MDA-MB-468 cells and selectively degrades BRD4 short isoform over long isoform in MDA-MB-231 cells. It also displays improved antiproliferative activity than dBET1. Overall, our study expands the limited toolbox for targeted protein degradation.

Platinum compounds (cisplatin and carboplatin) represent the most active anticancer agents in clinical use both of lung cancer in mono-and combination therapies. However, platinum resistance limits its clinical application. It is necessary to understand the molecular mechanism of platinum resistance, identify predictive markers, and develop newer, more effective and less toxic agents to treat platinum resistance in lung cancer. Here, it summarizes the main molecular mechanisms associated with platinum resistance in lung cancer and the development of new approaches to tackle this clinically relevant problem. Moreover, it could lead to the development of more effective treatment for refractory lung cancer in future., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Anticancer drugs are a group of therapeutic agents used to enhance cell death in targeted cell types of neoplasia. Because of frequent use and eventual discharge, they have been often detected in wastewater from pharmaceutical factories and hospitals, domestic wastewater, and surface waters. The occurrence of these drugs in aquatic ecosystems and their effects on aquatic organisms have been poorly characterized. This review focuses on the global occurrence of major classes of anticancer drugs in water and sediments of freshwater ecosystems and their ecotoxicological effects at different biological levels. While the availability of data is fairly limited, concentrations of most anticancer drugs range from < 2 ng/L to 762 µg/L in receiving water, while levels in sediments and sludge vary from 0.25 to 42.5 µg/kg. Their detection frequencies were 58%, 52% (78%) and 59% in hospital wastewater, wastewater treatment plant effluents (influents) and surface water, respectively. Predicted log K ow values of vincristine, imatinib mesylate and tamoxifen are higher than 3 and have estimated half-lives>60 d in waters using quantitative structure-activity relationship models, indicating high potential for persistence and bioaccumulation. Based on a species sensitivity distribution evaluation of 9 compounds, crustaceans are most sensitive to anticancer drugs. The most hazardous compound is cisplatin which has a hazard concentration at the 5th percentile. For Daphnia magna, the acute toxicities of major classes of anticancer drugs are ranked as platinum complexes > endocrine therapy agents > antibiotics > antimetabolite agents > alkylating agents. Using hazard quotient analysis based primarily on the lowest observed effect concentrations (LOECs), cyclophosphamide, cisplatin, 5-fluorouracil, imatinib mesylate, bicalutamide, etoposide and paclitaxel have the highest hazard for aquatic organisms. Further research is needed to identify appropriate chronic endpoints for risk assessment thresholds as well as to better understand the mechanisms of action and the potential multigenerational toxicity, and trophic transfer in ecosystems., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Ribonucleotide reductase (RR) is a unique enzyme for the reduction of NDPs to dNDPs, the building blocks for DNA synthesis and thus essential for cell proliferation. Pan-cancer profiling studies showed that RRM2, the small subunit M2 of RR, is abnormally overexpressed in multiple types of cancers; however, the underlying regulatory mechanisms in cancers are still unclear. In this study, through searching in cancer-omics databases and immunohistochemistry validation with clinical samples, we showed that the expression of MYBL2, a key oncogenic transcriptional factor, was significantly upregulated correlatively with RRM2 in colorectal cancer (CRC). Ectopic expression and knockdown experiments indicated that MYBL2 was essential for CRC cell proliferation, DNA synthesis, and cell cycle progression in an RRM2-dependent manner. Mechanistically, MYBL2 directly bound to the promoter of RRM2 gene and promoted its transcription during S-phase together with TAF15 and MuvB components. Notably, knockdown of MYBL2 sensitized CRC cells to treatment with MK-1775, a clinical trial drug for inhibition of WEE1, which is involved in a degradation pathway of RRM2. Finally, mouse xenograft experiments showed that the combined suppression of MYBL2 and WEE1 synergistically inhibited CRC growth with a low systemic toxicity in vivo. Therefore, we propose a new regulatory mechanism for RRM2 transcription for CRC proliferation, in which MYBL2 functions by constituting a dynamic S-phase transcription complex following the G1/early S-phase E2Fs complex. Doubly targeting the transcription and degradation machines of RRM2 could produce a synthetic inhibitory effect on RRM2 level with a novel potential for CRC treatment.

In situ self-assembly of prodrug molecules into nanomedicine can elevate the therapeutic efficacy of anticancer medications by enhancing the targeting and enrichment of anticancer drugs at tumor sites. However, the disassembly and biodegradation of nanomedicine after enrichment prevents the further improvement of the efficiency, and avoiding such disassembly and biodegradation remains a challenge. Herein, we rationally designed a tandem molecular self-assembling prodrug that could selectively improve the therapeutic efficacy of HCPT against lung cancer by two orders of magnitude. The tandem molecular self-assembly utilized an elevated level of alkaline phosphatase and reductase in lung cancer cells. The prodrug first self-assembled into nanofibers by alkaline phosphatase catalysis and was internalized more efficiently by lung cancer cells than free HCPT. The resulting nanofiber was next catalyzed by intracellular reductase to form a more hydrophobic nanofiber that prevented the disassembly and biodegradation, which further significantly improved the efficacy of HCPT against lung cancer both in vitro and in vivo.

The antiproliferative activity of three cyclometalated Ru(II) complexes with the formula [Ru(bpy) 2 L]PF 6 , where bpy = 2,2'-bipyridine, Ru1: L1 = phenanthro[4,5-fgh]quinoxaline; Ru2: L2 = benzo[f]naphtho[2,1-h]quinoxaline; and Ru3: L3 = phenanthro[9,10-b]pyrazine, have been synthesized and characterized. The lipophilicity of the three Ru(II) complexes was modulated by the alteration of the planarity in the ligands of the complexes. With appropriate lipophilicity, Ru1-Ru3 exhibited mitochondrial accumulating property and cytotoxic activity against a spectrum of cancer cell lines. The underlying mechanism study indicated that these Ru(II) complexes can selectively accumulate in mitochondria and disrupt physiological processes, including the redox balance and energy generation in cancer cells. Elevation of iron content in triple-negative breast cancer (MDA-MB-231 cells) was observed after treatment with Ru(II) complexes, which may contribute to the production of reactive oxygen species (ROS) via Fenton reaction chemistry. Besides, the Ru(II) complexes decreased the intracellular glutathione (GSH) in cancer cells, leading to the failure in the cells to combat oxidative damage. Both of the mentioned processes contribute to the high oxidative stress and eventually lead to cancer cell death. On the other hand, Ru1-Ru3 significantly induced the depletion of adenosine triphosphate (ATP), causing disturbance of energy generation. Moreover, the results of wound-healing assay and transwell invasion assay, as well as the tube formation assay indicated the anti-migration and anti-angiogenesis properties of Ru1-Ru3. Our study demonstrated that these Ru(II) complexes are promising chemotherapeutic agents with oxidative stress induction and energy generation disturbance., (Copyright © 2021. Published by Elsevier Inc.)

Immunogenic cell death (ICD) is a vital component of therapeutically induced anti-tumor immunity. An iridium(III) complex (Ir1), containing an N,N-bis(2-chloroethyl)-azane derivate, as an endoplasmic reticulum-localized ICD inducer for non-small cell lung cancer (NSCLC) is reported. The characteristic discharge of damage-associated molecular patterns (DAMPs), that is, cell surface exposure of calreticulin (CRT), extracellular exclusion of high mobility group box 1 (HMGB1), and ATP, were generated by Ir1 in A549 lung cancer cells, accompanied by an increase in endoplasmic reticulum stress and reactive oxygen species (ROS). The vaccination of immunocompetent mice with Ir1-treated dying cells elicited an antitumor CD8 + T cell response and Foxp3 + T cell depletion, which eventually resulted in long-acting anti-tumor immunity by the activation of ICD in lung cancer cells. Ir1 is the first Ir-based complex that is capable of developing an immunomodulatory response by immunogenic cell death., (© 2020 Wiley-VCH GmbH.)

Lupeol is a natural triterpenoid that widely exists in edible fruits and vegetables, and medicinal plants. In the last decade, a plethora of studies on the pharmacological activities of lupeol have been conducted and have demonstrated that lupeol possesses an extensive range of pharmacological activities such as anticancer, antioxidant, anti-inflammatory, and antimicrobial activities. Pharmacokinetic studies have indicated that absorption of lupeol by animals was rapid despite its nonpolar characteristics, and lupeol belongs to class II BCS (biopharmaceutics classification system) compounds. Moreover, the bioactivities of some isolated or synthesized lupeol derivatives have been investigated, and these results showed that, with modification to C-3 or C-19, some derivatives exhibit stronger activities, e.g., antiprotozoal or anticancer activity. This review aims to summarize the advances in pharmacological and pharmacokinetic studies of lupeol in the last decade with an emphasis on its anticancer and anti-inflammatory activities, as well as the research progress of lupeol derivatives thus far, to provide researchers with the latest information, point out the limitations of relevant research at the current stage and the aspects that should be strengthened in future research., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Drug-resistant mutations constitute a significant cause of crizotinib treatment failure for non-small cell lung cancer, which poses a major clinical challenge in the successful treatment of non-small cell lung cancer; therefore, the discovery of the resistance mechanisms of crizotinib is of utmost importance. Understanding the acquired BRAF 600E mutation is essential for designing new effective therapeutic combinations against disease progression., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: To investigate the effects and the mechanisms of action of Diallyl trisulfide (DATS) on the proliferation and metastasis of human osteosarcoma (OS) U2OS., Methods: U2OS cells were treated by different concentrations of DATS at different time points. Cell proliferations were measured by MTT assay. DATS induced cell cycle distribution and apoptosis were evaluated by flow cytometry (FCM) with Annexin-V. Cell migration and invasion were detected by wound healing assay and transwell assay. The effects of DATS in U2OS cell growth and metastasis were also detected in a mouse OS xenograft model., Results: A time- and concentration-dependent cytotoxic effect of DATS was observed in U2OS cells. FCM with PI staining and Annexin-V -FITC indicated that DATS induces apoptosis and a G0/G1 cell cycle arrest of U2OS cells at all concentrations from 25 μmol/l to 100 μmol/l. DATS also inhibits the migration and invasion of U2OS cells. Western blot showed that the expression levels of p-AKT, p-GSK3β, Bcl-2, Vimentin and β-catenin were decreased, while the expression levels of Bad, Bax and E-cadherin were significantly increased in DATS treated U2OS cells. Analysis using a mouse xenograft model indicated that xenografts of DATS treatment group had a significant decrease in tumor volume and weight compared to the control group. Lung metastasis models in mice demonstrated that treatment of DATS inhibits lung metastasis of OS in vivo., Conclusions: These data suggested that DATS inhibits OS development and progression through the regulation of PI3K/AKT/GSK3β signaling pathways, accompanied by downregulation of Bcl-2, Vimentin and β-catenin, as well as upregulation of Bad, Bax and E-cadherin. Therefore, our data demonstrated that DATS exerted its anticancer effects by inhibiting cell proliferation, migration and invasion in vitro and in vivo. These results provide evidence for the use of the natural product DATS either alone or in combination with standard therapy for OS.

Aberrant signal transducer and activator of transcription 3 (STAT3) signaling promotes the initiation and progression of cancer in humans by either inhibiting apoptosis or inducing cell proliferation, angiogenesis, invasion, and metastasis. The role of resveratrol（RES）in inhibiting the STAT3 signaling pathway in vivo, particularly in cervical cancer is still unknown. This study aims to investigate the role of STAT3 and its phosphorylation in RES-mediated suppression of cervical cancer. The effects of RES on cervical cancer were determined by examining tumor tissues, their histological changes, and the volume and weight of tumor tissues grown from HeLa cells injected in female athymic BALB/C nude mice. The structure and target interaction of RES were virtually screened using the molecular docking program Autodock Vina. The status of phosphorylated STAT3, protein levels of epithelial-mesenchymal transition molecular markers and extracellular matrix degradation enzymes were determined through Western blot. We demonstrated that RES could suppress the proliferation and metastatic potential of cervical cancer cells by inactivating phosphorylation of STAT3 at Tyr705 but not Ser727. This effect was intensified by inhibition of the STAT3 signal pathway., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Cardiovascular dysfunction is one of the most common complications of long-term cancer treatment. Growing evidence has shown that antineoplastic drugs can increase cardiovascular risk during cancer therapy, seriously affecting patient survival. However, little is known about the genetic factors associated with the cardiovascular risk of antineoplastic drugs. We established a compendium of genetic evidence that supports cardiovascular risk induced by antineoplastic drugs. Most of this genetic evidence is attributed to causal alleles altering the expression of cardiovascular disease genes. We found that antineoplastic drugs predicted to induce cardiovascular risk are significantly enriched in drugs associated with cardiovascular adverse reactions, including many first-line cancer treatments. Functional experiments validated that retinoid X receptor agonists can reduce triglyceride lipolysis, thus modulating cardiovascular risk. Our results establish a link between the causal allele of cardiovascular disease genes and the direction of pharmacological modulation, which could facilitate cancer drug discovery and clinical trial design., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

After an osteosarcoma resection, the risks of cancer recurrence, postoperative infection, and large bone loss still threaten patients' health. Conventional treatment relies on implanting orthopedic materials to fill bone defects after surgery, but it has no ability of destroying residual tumor cells and preventing bacterial invasion. To tackle this challenge, here, we develop a novel multifunctional implant (SP@MX/GelMA) that mainly consists of MXene nanosheets, gelatin methacrylate (GelMA) hydrogels, and bioinert sulfonated polyetheretherketone (SP) with the purpose of facilitating tumor cell death, combating pathogenic bacteria, and promoting osteogenicity. Because of the synergistic photothermal effects of MXene and polydopamine (pDA), osteosarcoma cells are effectively killed on the multifunctional coatings under 808 nm near-infrared (NIR) irradiation through thermal ablation. After loading tobramycin (TOB), the SP@MX-TOB/GelMA implants display robust antibacterial properties against Gram-negative/Gram-positive bacteria. More importantly, the multifunctional implants are demonstrated to have superior cytocompatibility and osteogenesis-promoting capability in terms of cell replication, spreading, alkaline phosphatase activity, calcium matrix mineralization, and in vivo osseointegration. Accordingly, such photothermally controlled multifunctional implants not only defeat osteosarcoma cells and bacteria but also intensify osteogenicity, which hold a greatly promising countermeasure for curing postoperative tissue lesion from an osteosarcoma excision.

The incidence of triple-negative breast cancer (TNBC) is difficult to predict, and TNBC has a high mortality rate among women worldwide. In this study, a theranostics approach is developed for TNBC with ratiometric photoacoustic monitored thiol-initiated hydrogen sulfide (H 2 S) therapy. The ratiometric photoacoustic (PA) probe (CY) with a thiol-initiated H 2 S donor (PSD) to form a nanosystem (CY-PSD nanoparticles) is integrated. In this theranostics approach, H 2 S generated from PSD is sensed by CY based on ratiometric PA signals, which simultaneously pinpoints the tumor region. Additionally, H 2 S is cytotoxic toward TNBC cells (MDA-MB 231), showing a tumor inhibition rate of 63%. To further verify its pharmacological mechanism, proteomics analysis is performed on tumors treated with CY-PSD nanoparticles. Cells are killed by the significant mitochondrial dysfunction via supressed energy supply and apoptosis initiation. Besides, the observed inhibition of oxidative stress also generates the cytotoxicity. Significant Kyoto Encyclopedia of Genes Genomes pathways related to TNBC are found to be inhibited. This H 2 S theranostics approach updates the current anticancer therapies which brings promise for women suffering malignant breast cancer., (© 2020 Wiley-VCH GmbH.)

Aims: Berberine is an isoquinoline alkaloid extracted from the root, rhizome and stem bark of Coptidis Rhizoma. Previous studies have revealed the anti-tumor potential of berberine against various types of cancer cells. However, the underlying mechanisms are not yet fully understood. In this study, we focused on the effects of berberine on fatty acid synthesis and extracellular vesicles formation in cancer cells, and revealed the internal mechanism of berberine inhibition on cancer cell proliferation., Materials and Methods: Anti-proliferative activity of berberine was determined by cell counting and microscope observation and cell cycle analysis. Activities of AMPK and ACC, expression of extracellular vesicles markers were detected by western blotting. 13 C labeling metabolic flux analysis was used for determination of de novo synthesis of fatty acids. The excreted extracellular vesicles in culture mediums were separated by both polyethylene glycol enrichment of extracellular vesicles and differential centrifugation separation., Key Findings: Among our early experiments, 5-10 μmol/L berberine exhibited the substantial anti-proliferative effect against human colon cancer cell line HCT116, cervical cancer cell line HeLa and other cancer cells. It was also revealed that, through activating AMPK, berberine inhibited ACC activity then suppressed intracellular fatty acid synthesis, finally decreased the biogenesis of extracellular vesicles. Moreover, supplement with citrate acid, palmitic acid, as well as exogenous extracellular vesicles, could rescue the inhibitory effect of berberine on cell proliferation, suggesting that inhibited ACC activity, suppressed fatty acid synthesis and decreased extracellular vesicles production were important mechanisms account for berberine inhibiting cancer cell proliferation., Significance: Our study indicates that berberine suppresses cancer cell proliferation through inhibiting the synthesis of fatty acids and decreasing biogenesis and secretion of extracellular vesicles, suggests that berberine is a promising candidate for the development of new therapies for cancer., Competing Interests: Declaration of competing interest None., (Copyright © 2020. Published by Elsevier Inc.)

Rationale: Neoadjuvant chemotherapy has become the standard treatment of locally advanced breast cancer. Antimicrotubule drugs and DNA-damaging drugs are the most popular medicines used for neoadjuvant chemotherapy. However, we are unable to predict which chemotherapeutic drug will benefit to an individual patient. PARK2 as a tumor suppressor in breast cancer has been reported. While the role of PARK2 in chemotherapy response remains unknown. In this study, we explore the impact of PARK2 on chemosensitivity in breast cancer. Methods: PARK2 expression in breast cancer patients with different neoadjuvant chemotherapeutic regimens was studied using immunohistochemistry. Data was correlated to disease-free survival (DFS), overall survival and pathologic complete response (pCR). The functional roles of PARK2 were demonstrated by a series of in vitro and in vivo experiments. Including mass spectrometry, Co-immunoprecipitation, isolation of subcellular fractionation, fluorescence microscopy, in vivo ubiquitination assay and luciferase analyses. Results: Highly expressed PARK2 predicted better response to antimicrotubule drugs-containing regimen associated with higher rate of pathologic complete response (pCR). In contrast, PARK2 expression did not predict response to the DNA-damaging drugs regimen. Following antimicrotubule drugs treatment, levels of PARK2 was upregulated due to the repression of STAT3-mediated transcriptional inhibition of PARK2. Moreover, overexpression of PARK2 specifically rendered cells more sensitive to antimicrotubule drugs, but not to DNA-damaging drugs. Depletion of PARK2 enhanced resistance to antimicrotubule drugs. Mechanistically, PARK2 markedly activated the mitochondrial pathway of apoptosis after exposure to antimicrotubule drugs. This occurred through downregulating the antiapoptotic protein, phospho-BCL-2. BCL-2 phosphorylation can be specifically induced by antimicrotubule drugs, whereas DNA-damaging drugs do not. Notably, PARK2 interacted with phospho-BCL-2 (Ser70) and promoted ubiquitination of BCL-2 in an E3 ligase-dependent manner. Hence, PARK2 significantly enhanced the chemosensitivity of antimicrotubule drugs both in vitro and in vivo , while loss-of-function PARK2 mutants did not. Conclusions: Our findings explained why PARK2 selectively confers chemosensitivity to antimicrotubule drugs, but not to DNA-damaging drugs. In addition, we identified PARK2 as a novel mediator of antimicrotubule drugs sensitivity, which can predict response of breast cancer patients to antimicrotubule drugs-containing regime., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

MCL1 has critical antiapoptotic functions and its levels are tightly regulated by ubiquitylation and degradation, but mechanisms that drive this degradation, particularly in solid tumors, remain to be established. We show here in prostate cancer cells that increased NOXA, mediated by kinase inhibitor activation of an integrated stress response, drives the degradation of MCL1, and identify the mitochondria-associated ubiquitin ligase MARCH5 as the primary mediator of this NOXA-dependent MCL1 degradation. Therapies that enhance MARCH5-mediated MCL1 degradation markedly enhance apoptosis in response to a BH3 mimetic agent targeting BCLXL, which may provide for a broadly effective therapy in solid tumors. Conversely, increased MCL1 in response to MARCH5 loss does not strongly sensitize to BH3 mimetic drugs targeting MCL1, but instead also sensitizes to BCLXL inhibition, revealing a codependence between MARCH5 and MCL1 that may also be exploited in tumors with MARCH5 genomic loss., Competing Interests: SA, AV, MN, SC, LX, SB No competing interests declared, (© 2020, Arai et al.)

Lung cancer is the most common cancer and leading cause of cancer-related deaths worldwide. The first-generation reversible, ATP-competitive inhibitors gefetinib and elotinib showed good clinical responses in lung adenocarcinoma tumors (NSCLC). But almost all patients developed resistance to these inhibitors over time. Such resistance of EGFR inhibitors was frequently linked to the acquired L858R and T790M point mutations in the kinase domain of EGFR. To overcome these resistance problems, the second and the third generation inhibitors have been discovered. FDA approved afatinib, the second generation irreversible inhibitor and osimitinib, the third generation irreversible EGFR inhibitors for the treatments of NSCLC. We identified new covalent quinazoline inhibitors (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-ethoxyethoxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide (6d) and (E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-7-(2-ethoxyethoxy)quinazolin-6-yl)-4-(dimethyl-amino)but-2-enamide (6h) that exhibited potent EGFR kinase inhibitory activities on L858R and T790M mutations. The compound 6 h showed selectivity similar to AZD9291 (osimertinib) in mutated and wild type tumor cell lines. In vitro cell assay 6d and 6h were better than afatinib and osimertinib. In vivo antitumor efficacy studies of these compounds were done in NCI-H1975 mice xenografts., Competing Interests: Declaration of Competing Interest No., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Carrier-free nanoparticles (NPs) via chemotherapeutic drug-drug conjugate assembly are a promising alternative for tumor chemotherapy. However, these NPs are still hindered via their nonspecific internalization into certain healthy cells and tissues. Herein, dual-acting methotrexate (MTX) and mannose (MAN) were conjugated via a hydrolyzable ester bond to synthesize a MTX-MAN conjugate as one molecule, which could be directly self-assembled into stimulus-responsive carrier-free NPs (MTX-MAN NPs) in aqueous solution. Such carrier-free MTX-MAN NPs with an accurate drug to sugar ratio could achieve on-demand drug release by dual stimuli of lysosomal acidity and esterase. Besides, MTX-MAN NPs could be dual-recognized by tumor cells in vitro and specifically by tumors in vivo. Moreover, the large proportion of MAN located on the NPs' surface could exert a shielding effect to avoid phagocytosis of macrophages, leading to long blood circulation. Therefore, the MTX-MAN NPs sharply reduced the drug dosage and decreased the toxicity to normal cells and tissues. Further in vitro and in vivo studies consistently confirmed that the MTX-MAN NPs exhibited superior tumor accumulation and highly synergistic chemotherapeutic effects. Furthermore, we found for the first time that MAN could enhance the antitumor activity of MTX. Considering that bi-functional MTX and MAN are approved via the FDA, and MAN is highly biosafe, the dual-self-recognizing, stimulus-responsive, and carrier-free MTX-MAN NPs might be a simple, selective, and safe chemotherapeutic strategy.