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Context: Glioma, the most common primary malignant brain tumour, is a grave health concern associated with high morbidity and mortality. Current treatments, while effective to some extent, are often hindered by factors such as the blood-brain barrier and tumour microenvironment. This underscores the pressing need for exploring new pharmacologically active anti-glioma compounds., Methods: This review synthesizes information from major databases, including Chemical Abstracts, Medicinal and Aromatic Plants Abstracts, ScienceDirect, SciFinder, Google Scholar, Scopus, PubMed, Springer Link and relevant books. Publications were selected without date restrictions, using terms such as ' Hymenocrater spp.,' 'phytochemical,' 'pharmacological,' 'extract,' 'essential oil' and 'traditional uses.' General web searches using Google and Yahoo were also performed. Articles related to agriculture, ecology, synthetic work or published in languages other than English or Chinese were excluded., Results: The marine environment has been identified as a rich source of diverse natural products with potent antitumour properties., Conclusions: This paper not only provides a comprehensive review of marine-derived compounds but also unveils their potential in treating glioblastoma multiforme (GBM) based on functional classifications. It encapsulates the latest research progress on the regulatory biological functions and mechanisms of these marine substances in GBM, offering invaluable insights for the development of new glioma treatments.

ATR has emerged as a promising target for anti-cancer drug development. Several potent ATR inhibitors are currently undergoing various stages of clinical trials, but none have yet received FDA approval due to unclear regulatory mechanisms. In this study, we discovered a potent and selective ATR degrader. Its kinase-independent regulatory functions in acute myeloid leukemia (AML) cells were elucidated using this proteolysis-targeting chimera (PROTAC) molecule as a probe. The ATR degrader, 8 i, exhibited significantly different cellular phenotypes compared to the ATR kinase inhibitor 1. Mechanistic studies revealed that ATR deletion led to breakdown in the nuclear envelope, causing genome instability and extensive DNA damage. This would increase the expression of p53 and triggered immediately p53-mediated apoptosis signaling pathway, which was earlier and more effective than ATR kinase inhibition. Based on these findings, the in vivo anti-proliferative effects of ATR degrader 8 i were assessed using xenograft models. The degrader significantly inhibited the growth of AML cells in vivo, unlike the ATR inhibitor. These results suggest that the marked anti-AML activity is regulated by the kinase-independent functions of the ATR protein. Consequently, developing potent and selective ATR degraders could be a promising strategy for treating AML., (© 2024 Wiley‐VCH GmbH.)

In this study, we synthesized a novel compound, agmatine-cholesterol conjugate (AG-Chol), to enhance the anti-tumor activity of drug-loaded liposomes. We replaced cholesterol with AG-Chol in preparing doxorubicin hydrochloride (DOX) liposomes by using an active loading method for DOX. We assessed the physical and chemical properties of the resulting AG-Liposomes and evaluated their efficacy in vitro and in vivo. The results showed that AG-Liposomes were stable with high encapsulation efficiency. Compared with the control liposomes, AG-Liposomes exhibited a slower drug release rate in the release medium at pH 6.8. The in vitro cell experiments demonstrated that AG-Liposomes had higher tumor cell uptake rate, stronger migration inhibition rate, higher apoptosis rate, better anti-clonogenic ability, and higher lysosome escape ability than the control liposomes. In vivo distribution results demonstrate that liposomes prepared with AG-Chol instead of cholesterol can significantly enhance their tumor targeting abilities and reduce their distribution to non-targeted sites. In vivo tumor suppression experiments showed that AG-Liposomes had a higher tumor suppression rate than the control liposomes without causing apparent toxicity to normal tissues, as evidenced by histological staining. Therefore, substituting cholesterol with AG-Chol in the preparation of liposomes can result in enhanced lysosome escape, improved tumor targeting, and increased efficacy of anti-tumor drugs., (© 2023. Controlled Release Society.)

Chelerythrine chloride (CHE) is a quaternary benzo[ c ]phenanthridine alkaloid with an iminium group that was found to cause time- and concentration-dependent inhibition of CYP3A4. The loss of CYP3A4 activity was independent of NADPH. CYP3A4 competitive inhibitor ketoconazole and nucleophile N -acetylcysteine (NAC) slowed the inactivation. No recovery of CYP3A4 activity was observed after dialysis. Dihydrochelerythrine hardly inhibited CYP3A4, suggesting that the iminium group was primarily responsible for the inactivation. UV spectral analysis revealed that the maximal absorbance of CHE produced a significant red-shift after being mixed with NAC, suggesting that 1,2-addition possibly took place between the sulfhydryl group of NAC and iminium group of CHE. Molecular dynamics simulation and site-direct mutagenesis studies demonstrated that modification of Cys239 by the iminium group of CHE attributed to the inactivation. In conclusion, CHE is an affinity-labeling inactivator of CYP3A4. The observed enzyme inactivation resulted from the modification of Cys239 of CYP3A4 by the iminium group of CHE.

Mutation burden, hypoxia, and immunoediting contribute to altered metabolic profiles in tumor cells, resulting in a tumor microenvironment (TME) characterized by accumulation of toxic metabolites and depletion of various nutrients, which significantly hinder the antitumor immunity via multiple mechanisms, hindering the efficacy of tumor immunotherapies. In-depth investigation of the mechanisms underlying these phenomena are vital for developing effective antitumor drugs and therapies, while the therapeutic effects of metabolism-targeting drugs are restricted by off-target toxicity toward effector immune cells and high dosage-mediated side effects. Nanotechnologies, which exhibit versatility and plasticity in targeted delivery and metabolism modulation, have been widely applied to boost tumor immunometabolic therapies via multiple strategies, including targeting of metabolic pathways. In this review, recent advances in understanding the roles of tumor cell metabolism in both immunoevasion and immunosuppression are reviewed, and nanotechnology-based metabolic reprogramming strategies for enhanced tumor immunotherapies are discussed.

Since the first natural carbazole alkaloid, murrayanine, was isolated from Mwraya Spreng, carbazole alkaloid derivatives have been widely concerned for their anti-tumor, anti-viral and anti-bacterial activities. In recent decades, a growing body of data suggest that carbazole alkaloids and their derivatives have different biological activities. This is the first comprehensive description of the antifungal and antibacterial activities of carbazole alkaloids in the past decade (2012-2022), including natural and partially synthesized carbazole alkaloids in the past decade. Finally, the challenges and problems faced by this kind of alkaloids are summarized. This paper will be helpful for further exploration of this kind of alkaloids., 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 © 2023 Elsevier Masson SAS. All rights reserved.)

Recently, histone lysine specific demethylase 1 (LSD1) has become an emerging and promising target for cancer immunotherapy. Herein, based on our previously reported LSD1 inhibitor DXJ-1 (also called 6x), a series of novel acridine-based LSD1 inhibitors were identified via structure optimizations. Among them, compound 5ac demonstrated significantly enhanced inhibitory activity against LSD1 with an IC 50 value of 13 nM, about 4.6-fold more potent than DXJ-1 (IC 50  = 73 nM). Molecular docking studies revealed that compound 5ac could dock well into the active site of LSD1. Further mechanism studies showed that compound 5ac inhibited the stemness and migration of gastric cancer cells, and reduced the expression of PD-L1 in BGC-823 and MFC cells. More importantly, BGC-823 cells were more sensitive to T cell killing when treated with compound 5ac. Besides, the tumor growth was also suppressed by compound 5ac in mice. Together, 5ac could serve as a promising candidate to enhance immune response in gastric cancer., 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 © 2023. Published by Elsevier Masson SAS.)

Carboxymethyl pachymaran (CMP) was treated via high-temperature and cellulase hydrolysis to obtain HTCMP, HTEC-24, and HTEC-48. The chemical structure and in vivo antitumor activities of the four types of CMPs were investigated. Compared with CMP (787.9 kDa), the molecular weights of HTCMP, HTEC-24, and HTEC-48 were decreased to 429.8, 129.9, and 68.6 kDa, respectively. The viscosities and particle sizes of the CMPs could also decrease with the decline in the molecular weights. All the CMPs showed antitumor abilities, but HTEC-24 exhibited the best activity. In the animal study, when curing the spleen and thymus, CMPs displayed immunomodulatory effects by increasing the secretion of IFN-γ and IL2 in mice. The CMPs also exerted an antitumor ability by regulating the gut microbiota in tumor-bearing mice. Our results established a foundation to develop an antitumor drug with CMP.

Primary liver cancer is one of the most common malignant cancers of the digestive system that lacks effective chemotherapeutic drugs in clinical settings. Camptothecin (CPT) and its derivatives have been approved for cancer treatment; however, their application is limited by their systemic toxicity. For lead optimization in new drug discovery stages, fluorination is an effective and robust approach to increase the bioavailability and optimize the pharmacokinetics of candidate compounds, thereby improving their efficacy. To obtain new and highly active CPT derivatives, we designed, synthesized, and evaluated two new fluorinated CPT derivatives, 9-fluorocamptothecin (A1) and 7-ethyl-9-fluorocamptothecin (A2), in this study. In vitro, A1 and A2 exhibited more robust anti-tumor activity than topotecan (TPT) in various cancer cells, particularly hepatocellular carcinoma (HCC) cells. In vivo, A1 and A2 exhibited greater anti-tumor activity than TPT in both AKT/Met induced primary HCC mouse models and implanted HepG2 cell xenografts. Acute toxicity tests revealed that A1 and A2 were not lethal and did not cause significant body weight loss at high doses. Moreover, A1 and A2 exhibited no significant toxicity in the mouse liver, heart, lung, spleen, kidney, and hematopoietic systems at therapeutic doses. Mechanistically, A1 and A2 blocked HCC cell proliferation by inhibiting the enzymatic activity of Topo I, subsequently inducing DNA damage, cell cycle arrest, and apoptosis. In summary, our results indicate that fluorination improves the anti-tumor activity of CPT while decreasing its toxicity and highlight the application potential of fluorination products A1 and A2 in clinical settings., 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 © 2023 Elsevier Inc. All rights reserved.)

Colorectal cancer (CRC) is one of the most common malignant tumors with a high lethal rate globally, and novel strategies for its prevention and therapy are urgently needed. In our previous work, 8-methoxyflindersine (8-MF), a quinoline alkaloid, was isolated from the Dictamni cortex, and its bioactivities were largely unknown. In this study, we found that 8-MF significantly inhibited cell viability in the CRC cell lines LoVo and RKO. The 8-MF-induced CRC cell apoptosis, as well as cell cycle disorder, were further verified by cyclins dysregulation in mRNA and protein levels. Further, the activation of MAPK family members p38 and ERK1/2 was observed after 8-MF treatment. Moreover, the protein-protein interaction of 8-MF with cyclins and MAPKs was demonstrated using the STRING database. The 8-MF could bind to p38 and ERK1/2 proteins in molecular docking. Taken together, we found that 8-MF induced apoptosis and cell cycle disorder involving MAPK signaling activation in CRC cells, indicating 8-MF as a novel lead compound candidate for the development of anti-tumor drugs for CRC., Competing Interests: The authors declare no conflict of interest.

Scalable production of a clinically translatable formulation with enhanced therapeutic efficacy against cisplatin-resistant tumors without the use of any clinically unapproved reagents and additional manipulation remains a challenge. For this purpose, we report herein the construction of TPP-Pt- acetal -CA based on all commercially available, clinically approved reagents consisting of a cinnamaldehyde (CA) unit for reactive oxygen species generation, a mitochondrially targeted triphenylphosphonium (TPP)-modified Pt(IV) moiety for mitochondrial dysfunction, and an intracellular acidic pH-cleavable acetal link between these two moieties. The resulting self-assembled, stabilized TPP-Pt- acetal -CA nanoparticles mediated an IC 50 value approximately 6-fold lower than that of cisplatin in A549/DDP cells and a tumor weight reduction 3.6-fold greater than that of cisplatin in A549/DDP tumor-bearing BALB/c mice with insignificant systematic toxicity due to the synergistic mitochondrial dysfunction and markedly amplified oxidative stress. Therefore, this study presents the first example of a clinically translatable Pt(IV) prodrug with enhanced efficiency for synergistically reversing drug resistance.

Objective: This study evaluated the antitumor activity and safety of pemigatinib in previously treated Chinese patients with advanced cholangiocarcinoma and fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements., Background: Pemigatinib provided clinical benefits for previously treated patients with cholangiocarcinoma carrying FGFR2 fusions or rearrangements and was approved for this indication in multiple countries., Methods: In this ongoing, multicenter, single-arm, phase II study, adult patients with locally advanced or metastatic cholangiocarcinoma carrying centrally confirmed FGFR2 fusions or rearrangements who had progressed on ≥1 systemic therapy received 13.5 mg oral pemigatinib once daily (3-week cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was objective response rate (ORR) assessed by an independent radiology review committee., Results: As of January 29, 2021, 31 patients were enrolled. The median follow-up was 5.1 months (range, 1.5-9.3). Among 30 patients with FGFR2 fusions or rearrangements evaluated for efficacy, 15 patients achieved partial response (ORR, 50.0%; 95% confidence interval [CI], 31.3-68.7); 15 achieved stable disease, contributing to a disease control rate of 100% (95% CI, 88.4-100). The median time to response was 1.4 months (95% CI, 1.3-1.4), the median duration of response was not reached, and the median progression-free survival was 6.3 months (95% CI, 4.9-not estimable [NE]). Eight (25.8%) of 31 patients had ≥grade 3 treatment-emergent adverse events. Hyperphosphatemia, hypophosphatasemia, nail toxicities, and ocular disorders were mostly

Phthalidyl promoiety has been used in several drugs, but they were all marketed in racemic form. The pharmaceutical effects of each enantiomer have not been clearly demonstrated. In this project, an anticancer chemotherapy drug, chlorambucil, was modified as enantiopure phthalidyl prodrugs. The enantiomers, together with phthalidyl unit and their racemic mixture, were then subject to the in vivo bioactivity tests against B16F10 melanoma cells. It was found that proper chirality within the promoiety had noticeably better in vivo pharmacological effects than the parent drug, the enantiomer and racemic mixture. This merit perhaps could be extended from the phthalidyl prodrugs to other chirality containing prodrugs., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

The incidence of various types of cancers is increasing every year. Among these, leukemia is extremely common, and thus, developing novel drugs to combat leukemia is crucial. In this study, we designed and synthesized several hybrids and obtained a new lead molecule 5a, with a strong therapeutic effect on leukemia. The results indicated that most hybrids effectively inhibited the growth of leukemia cells, HCT-116, and A549 cancer cells with an IC 50 of <10 μM. Among these hybrids, 5a and 4h showed significant anticancer activity against CCRF-CEM, with IC 50 values of 0.895 μM and 0.555 μM, respectively. Particularly, 5a had lower toxicity to L02 than chlorambucil (CLB) and doxorubicin (Dox), and the high selectivity was also reflected in the normal human B lymphoblast cell line (IM9). Upon investigating the mechanism of action, we found that 5a downregulated Bcl-2 and caused DNA double-stranded breaks (DSBs) to induce several genotoxic stress responses. The results of the flow cytometry assay showed that 5a was a non-specific molecule in the cell cycle. Furthermore, 5a did not affect total ROS levels but significantly improved the activity of glutathione peroxidase (GPx). Preliminary studies showed that nitrogen mustard exerted an efficient effect, and 5a can combine the advantages of artemisinin and nitrogen mustard and exhibit effects superior to either. This study showed that 5a should be further investigated as a therapeutic compound against leukemia., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dequn Sun Tianzhi Dai reports equipment, drugs, or supplies was provided by China Academy of Engineering Physics Institute of Materials., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Aims: In this study, we synthesized a 10-fluorine-substitution derivative of CPT (Camptothecin) YCJ100 and evaluated its antitumor activity and systemic toxicity., Materials and Methods: Determination of in vitro antitumor activity and mechanism of YCJ100 by the MTT assay, Molecular docking, EdU staining, Cell cycle and apoptosis determination, Western blot analysis and Topoisomerase I activity assay. The antitumor effects of YCJ100 were evaluated in primary HCC (hepatocellular carcinoma), ICC (intrahepatic cholangiocarcinoma) mouse models, and pancreatic cancer xenograft models., Key Findings: YCJ100 showed superior cytotoxic activity compared to Topotecan in SW480, SW1990, Hep3B, HepG2, A549, A2780, HeLa, and QBC cells. YCJ100 blocked the cell cycle in the G2/M phase, inhibited cell proliferation and induced apoptosis in HepG2 and SW1990 cells. Mechanistically, YCJ100 inhibited topoisomerase I activity in both a cell-free system and a cellular system, similar to the mechanism of Topotecan. YCJ100 showed significant antitumor activity and was more potent than Topotecan in primary HCC and ICC mouse models, as well as a xenograft mouse model. Additionally, YCJ100 showed only minor toxicity to the mouse hematopoietic system, liver, and kidney. These findings indicate that YCJ100 has high antitumor activity and low systemic toxicity., Significance: Our findings demonstrate that YCJ100, as a Topoisomerase I inhibitor, has in vitro and in vitro antitumor activity. This study provides a new lead compound worthy of further preclinical evaluation and potential clinical development., 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 © 2022. Published by Elsevier Inc.)

Curcumin has a wide range of pharmacological activities, which can be used to treat tumors, inflammation and other diseases. However, curcumin's poor solubility and low bioavailability limit its application. In this article, the structure of curcumin was modified with boron trifluoride ether to change fluorescent labeling. The compounds were then embedded into the hydrophobic cavity of α-cyclodextrin and hydroxypropyl β-cyclodextrin to form inclusion complexes. The two inclusion complexes have excellent photophysical properties, and the maximum emission wavelength is in the range of 550-565 nm. In addition, the two compounds were applied to the fluorescence imaging of HCT-116 cells and HeLa cells, and the proliferation toxicity of the compounds was detected. Both compounds showed certain inhibitory effects on the proliferation of cancer cells. In short, the fluorescent drug molecule synthesized in this article has great reference value for the development of new dosage forms of curcumin., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

This study aims to investigate the effect of ethoxysanguinarine(Eth) on cisplatin(DDP)-resistant human gastric cancer cells and decipher the underlying mechanism. The human gastric cancer cell line SGC7901 and the DDP-resistant cell line SGC7901/DDP were used as the cell models. Western blot was employed to determine the expression levels of multidrug resistance-related proteins, and methyl thiazolyl tetrazolium(MTT) assay to detect the proliferation of SGC7901 and SGC7901/DDP cells exposed to DDP. After treatment with different concentrations of Eth, the proliferation of SGC7901 and SGC7901/DDP cells was detected by MTT assay, trypan blue exclusion assay, colony formation assay, and high-content imaging and analysis system. The apoptosis of SGC7901/DDP cells was detected by flow cytometry with Annexin V-FITC/PI staining. GFP-LC3 transfection was carried out to detect the effect of Eth on the autophagy of SGC7901/DDP cells. The expression levels of the multidrug resistance-related protein P-glycoprotein(P-gp), the apoptosis-related proteins [caspase-9, caspase-3, and poly(ADP-ribose) polymerase(PARP)], the autophagy-related protein light chain 3-Ⅱ(LC3-Ⅱ), the key effectors [mammalian target of rapamycin(mTOR), 70 kDa ribosomal protein S6 kinase(P70 S6 K), and 4 E binding protein 1(4 E-BP1)] of the mammalian target of rapamycin complex 1(mTORC1) signaling pathway, cancerous inhibitor of protein phosphatase 2A(CIP2A), and protein kinase B(Akt) were measured by Western blot. The mRNA level of CIP2A in the SGC7901/DDP cells exposed to Eth for 24 h was analyzed by RT-qPCR. After SGC7901/DDP cells were transfected with CIP2A expression vector pcDNA3.1-HA-CIP2A and treated with different concentrations of Eth, MTT assay was used to determine the prolife-ration of SGC7901/DDP cells and Western blot to detect the expression levels of related proteins. The interaction sites of Eth and CIP2A were predicted by molecular docking. The affinity between Eth and CIP2A was determined by drug affinity responsive target stability(DARTS) assay. The pharmacokinetic properties and drug-like activity of Eth were predicted by SwissADME. The results indicated that SGC7901/DDP cells were more sensitive to Eth than SGC7901 cells. Eth significantly inhibited proliferation and colony formation and changed the morphology, roundness, and area of SGC7901/DDP cells. Eth treatment caused the nucleus shrinking and significantly increased the apoptosis rate of the cells. Furthermore, Eth down-regulated the expression of caspase-9 and caspase-3 precursors and promoted the cleavage of PARP, which suggested that Eth induced the apoptosis of SGC7901/DDP cells. The GFP-LC3 in Eth-treated cells showed speckled aggregation. The up-regulated expression of LC3-Ⅱ by Eth indicated that Eth activated the autophagy of SGC7901/DDP cells. Eth down-regulated the expression of P-gp, the phosphorylation of mTOR, P70 S6K, and 4E-BP1, the expression of CIP2A, and the phosphorylation of Akt. Additionally, it increased the activity of PP2A, and had no significant effect on the expression of CIP2A in SGC7901/DDP cells. CIP2A overexpression antagonized the inhibition of cell proliferation and the activation of autophagy by Eth. Molecular docking suggested that Eth bound to CIP2A. The results of DARTS assay further proved the above binding effect. Eth has potential drug-like activity. The above results demonstrated that Eth inhibited the proliferation, induced the apoptosis, and activated the autophagy of SGC7901/DDP cells by targeting CIP2A and then down-regulating PP2A/mTORC1 signaling pathway. This study provided a new target for the treatment of cisplatin-resistant gastric cancer.

5-Fluorouracil (5-FU) is an effective anticancer drug widely used in cancer treatment. In this study, two 5-FU derivatives containing a spacer arm with the carboxylic group at the end were synthesized, which were linked to the carrier proteins to form 5-FU-protein conjugates used as the immunogens for the production of monoclonal antibody (mAb). Based on the produced mAb, the highly sensitive and specific enzyme-linked immunosorbent assay (ELISA) for 5-FU detection was established. The IC 50 and LOD values of the assay were found to be 19.5 ng mL -1 and 0.5 ng mL -1 , respectively. There was no cross-reactivity (CR) of the ELISA with cytosine, thymine and uracil, which avoided the interference from inherent pyrimidines. The CR values of the assay with three substitutes of 5-FU (tegafur, 5-fluoro-2'-deoxyuridine, carmofur) were within 9.7%-17.6%. The produced mAb was also applied in sample extraction. The immuno-affinity column capable specific capturing 5-FU was prepared by immobilizing the mAb on Sepharose-4B gel and filling into a SPE column. The recoveries of 5-FU in spiked samples measured by ELISA were 72.4%-90.7% with RSD of 3.6%-8.3%. Five blood samples collected from patients were extracted by immuno-affinity column, then measured by ELISA and confirmed by HPLC-MS/MS. There was a good correlation between HPLC-MS/MS and ELISA. It is demonstrated that the developed ELISA combined with immuno-affinity extraction can be a powerful alternative method for the detection of 5-FU in blood samples., (Copyright © 2022. Published by Elsevier B.V.)

5-Fluorouracil (5-FU) is an effective anticancer drug widely used in the world. To improve therapy efficiency and reduce side effects, it is very important to frequently detect the concentration of 5-FU in blood samples of patients. In this work, a new type of lateral flow immunochromatographic assay (LFIA) based on surface-enhanced Raman scattering (SERS) for ultrasensitive and specific detection of 5-FU in blood samples was developed. Au@Ag/Au nanoparticles (NPs) employing Au particles as the core and Ag/Au alloy as the shell were synthesized, characterized and used as the substrate in SERS-LFIA due to their high SERS enhancement and biocompatibility. The immunoprobe was made in the form of Au MBA @Ag/Au-Ab in which mercaptobenzoic acid (MBA, a common Raman active reporter) was embedded in the core-shell layer and the monoclonal antibody (mAb) against 5-FU was immobilized on the surface. The performance of SERS-LFIA was similar to that in colloidal gold based-LFIA, and the entire assay time was within 20 min. According to the color intensity on the testing (T) lines of LFIA strips visualized by eyes, the contents of 5-FU in the samples could be qualitatively or semi-quantitatively identified. Furthermore, by measuring the characteristic Raman intensities of MBA on T lines, quantitative detection of 5-FU in the samples were achieved. The IC 50 and limit of detection (LOD) of the LFIA for 5-FU were found to be 20.9 pg mL -1 and 4.4 pg mL -1 , respectively. There was no cross-reactivity (CR) of the LFIA with nine relative compounds, and the CR with cytosine, tegafur and carmofur were less than 4.5%. The recoveries of 5-FU from spiked blood samples were in the range of 78.6~86.4% with the relative standard deviation (RSD) of 2.69~4.42%. Five blood samples containing 5-FU collected from the Cancer Hospital were measured by SERS-LFIA, and the results were confirmed by LC-MS/MS. It was proven that the proposed method was able to simply and rapidly detect 5-FU in blood samples with high sensitivity, specificity, accuracy and precision.

A series of new 7-ethyl-10-fluoro-20-O-(cinnamic acid ester)-camptothecin derivatives were synthesized and evaluated for cytotoxicity against four human tumor cell lines including HepG2 (hepatocellular carcinoma), SW480 (colorectal cancer), A2780 (ovarian cancer), and Hucct1 (intrahepatic cholangiocarcinoma). The results of cytotoxic activities in vitro showed that most of the camptothecin derivatives harbor promising cytotoxic activity against tested tumor cell lines. Among them, compound XJS-11 exhibited broad-spectrum inhibitory activities against HepG2, SW480, A2780, and Hucct1 cell lines with IC 50 values of 0.03, 0.09, 0.22, and 0.32 μM, respectively. Further investigation demonstrated that compound XJS-11 exhibited more effective growth inhibition against a variety of human hepatoma cells (Sk-hep-1, Hep3B and Huh7) and lower cytotoxicity against immortalized normal human liver cell line L02 than the positive control topotecan. Especially, XJS-11 showed higher selective toxicity in two kinds of human hepatoma cells and immortalized normal human liver cell line (IC 50(L-02) /IC 50(HepG2)  = 113.20; IC 50(L-02) /IC 50(Hep3B)  = 85.60) than topotecan (IC 50(L-02) /IC 50(HepG2)  = 9.45; IC 50(L-02) /IC 50(Hep3B)  = 8.52). Mechanistically, XJS-11 induced cell cycle arrest and cell apoptosis in HepG2 and Hep3B cells by inhibiting Top I activity in a manner similar to that of topotecan. Meanwhile, XJS-11 could attenuate the tumor growth in both xenograft and primary HCC mouse models. In addition, the acute toxicity assay showed that XJS-11 did not cause lethality or significant body weight loss with a single intraperitoneal dose at 100 mg/kg or with an intraperitoneal dose at 25 mg/kg for 7 days. Moreover, unlike topotecan, XJS-11 had no apparent toxicity to the mouse liver, kidney, and hemopoietic system of the C57BL/6 mice. Taken together, XJS-11 merits further development as a new generation of the camptothecin-derived drug candidate., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Based on the structural skeleton of natural products boeravinones, two types of 6H-chromeno[3,4-b]quinoline derivatives were designed and synthesized by nitrogen atom substitution strategy. Then, their cytotoxic activities were evaluated against six human tumor cell lines including HepG2 (hepatocellular carcinoma), A2780 (ovarian cancer), Hela (cervical cancer), HCT116 (colorectal cancer), SW1990 (pancreatic cancer), and MCF7 (breast cancer). The results showed that compounds ZML-8 and ZML-14 exhibited robust inhibitory activities against HepG2 cells with IC 50 values of 0.58 and 1.94 μM, respectively. In addition, ZML-8 and ZML-14 showed higher selectivity against HepG2 and L-02 cells than Topotecan. Mechanistically, ZML-8 and ZML-14 not only induced cell cycle arrest in the G2/M phase and cell apoptosis, but also dose-dependently inhibited topoisomerase I activity and induced DNA damage in HepG2 cells. Molecular docking showed that ZML-8 and ZML-14 could interact with topoisomerase I-DNA complex with a similar binding mode to Topotecan. Inhibitory activities of these two compounds on topoisomerase I were then confirmed in both cell-free systems and in whole-cell lysates. Taken together, compounds ZML-8 and ZML-14 merit further development as a new generation of non-camptothecin topoisomerase I inhibitors for the treatment of cancer., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: MORC family CW-type zinc finger 2 (MORC2), a GHKL-type ATPase, is aberrantly upregulated in multiple types of human tumors with profound effects on cancer aggressiveness, therapeutic resistance, and clinical outcome, thus making it an attractive drug target for anticancer therapy. However, the antagonists of MORC2 have not yet been documented., Methods and Results: We report that MORC2 is a relatively stable protein, and the N-terminal homodimerization but not ATP binding and hydrolysis is crucial for its stability through immunoblotting analysis and Quantitative real-time PCR. The N-terminal but not C-terminal inhibitors of heat shock protein 90 (HSP90) destabilize MORC2 in multiple cancer cell lines, and strikingly, this process is independent on HSP90. Mechanistical investigations revealed that HSP90 N-terminal inhibitors disrupt MORC2 homodimer formation without affecting its ATPase activities, and promote its lysosomal degradation through the chaperone-mediated autophagy pathway. Consequently, HSP90 inhibitor 17-AAG effectively blocks the growth and metastatic potential of MORC2-expressing breast cancer cells both in vitro and in vivo, and these noted effects are not due to HSP90 inhibition., Conclusion: We uncover a previously unknown role for HSP90 N-terminal inhibitors in promoting MORC2 degradation in a HSP90-indepentent manner and support the potential application of these inhibitors for treating MORC2-overexpressing tumors, even those with low or absent HSP90 expression. These results also provide new clue for further design of novel small-molecule inhibitors of MORC2 for anticancer therapeutic application., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Rational designed lipid-drug derivatives provide a favorable approach to improve the druggability of highly hydrophobic prototypes. It has been regarded as common sense that good cytotoxicity is the guarantee of superior anticancer efficacy for candidate derivatives screening. However, does it apply to lipid-drug conjugate-based self-assembled nanoparticles? Here, we established the above two derivatives and a non-correlation between the cytotoxic activity in vitro and drug efficacy in vivo was found. The IC 50 of DSL NPs (DTX-S-LA nanoparticles) and DL NPs (DTX-LA nanoparticles) were 4.02 and 209.6 ng/mL (DTX equivalent concentration), respectively. However, DL NPs unexpectedly showed stronger tumor inhibition abilities than DSL NPs. To explain the non-positive correlation between cytotoxicity and anticancer efficacy, more experiments were carried out in depth. Remarkably, the drug release studies in blood and PK study both suggested that the DL NPs were more stable to remain the structural integrity in circulation, which resulted in more accumulation in tumor sites. As verified by the bio-distribution study, DL NPs performed a superior target effect than DSL NPs in tumors. Our data indicated that the biological fates of so-called smart bond inserted derivatives in vivo are complicated; thus, simple cytotoxicity is not enough for derivatives screening, and the comprehensive understanding of both in vitro and in vivo behaviors is essential., (© 2021. Controlled Release Society.)

Inspired by the biological use of a combination of precision and self-assembly to achieve exquisite control and diversity from 20 natural amino acids, there is considerable scope for the development of synthetic precision materials with complex architecture that can access advanced function for biomedical applications. Single cyclic polymers (SCPs) have been shown to offer different and often better performance compared to their linear analogues. Because multicyclic topology in nature offers enhanced effects relative to single cyclization, we hypothesize that multicyclic polymers (MCPs) would access unique features compared to SCPs. However, there are currently quite limited ways to efficiently synthesize MCPs and to precisely modulate the valency of cyclic units. In this work, we report for the first time a straightforward and robust strategy to synthesize MCPs with controllable valency via facile one-pot statistical reversible addition-fragmentation chain transfer (RAFT) copolymerization. We use this strategy to synthesize biocompatible MCPs based on the most classic and important biocompatible polymers of oligo (ethylene glycol) (OEG) and cyclic poly(ε-caprolactone) (cPCL), which can further self-assemble into well-defined nanostructures. We then apply these MCP-based formulations as drug delivery vehicles and demonstrate greater colloidal stability with a low critical micelle concentration (CMC) of 80.3 nM, larger drug loading capacity, higher cellular uptake efficiency, more tumor accumulation, and increased anti-tumor efficacy in murine tumor models compared to SCP-based analogues. We believe this cumulative work demonstrating facile synthesis of MCPs and demonstration of multicyclic topology-enhanced anti-cancer efficiency in vivo provides key technologies and concepts to the burgeoning field of cyclic topology-derived biomaterials., (Copyright © 2022. Published by Elsevier B.V.)

The rapid development of nanotechnology has generated numerous ideas for cancer treatment, and a wide variety of relevant nanoparticle platforms have been reported. Metal-organic frameworks (MOFs) have been widely investigated as an anti-cancer drug delivery vehicle owing to their unique porous hybrid structure, biocompatibility, structural tunability, and multi-functionality. MOF materials with catalytic activity, known as nanozymes, have applications in photodynamic and chemodynamic therapy. Nucleic acids have also attracted increasing research attention owing to their programmability, ease of synthesis, and versatility. A variety of functional DNAs and RNAs have been applied both therapeutically (gene-targeting drugs for cancer treatment) and nontherapeutically (used as modified materials to enhance the therapeutic effects of other nanomedicines). The combined use of MOFs and functional nucleic acids have been extensively investigated and has been associated with excellent tumor-suppressor activity in various treatment methods. In this review, we summarize the progress in the research and development of tumor therapy based on MOFs and nucleic acid delivery over recent years, focusing on the combinational use of different delivery and design strategies for MOF/therapeutic nucleic acid platforms. We further summarize the strategies for combining MOFs (universal carrier, functional carrier) and nucleic acids (therapeutic nucleic acids, nontherapeutic nucleic acids) and discuss the corresponding therapeutic effects in cancer treatment. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies., (© 2022 Wiley Periodicals LLC.)

Neocryptolepine derivatives have attracted great interest because of their unique cytotoxic activity. 8-Fluoroneocryptolepine (8FNC) was synthesized, and its cytotoxicity was evaluated by MTT assay in AGS gastric cancer cells and gastric mucosa GES-1 cells. 8-Fluoroneocryptolepine showed greater selectivity and cytotoxicity to AGS cells than the cisplatin (CIS) and fluorouracil (5-Fu) commonly used in clinical treatment of gastric cancer. Most importantly, we significantly improved the cytotoxic effect of 8FNC against AGS cells by structural modification and reduced the cytotoxicity against GES-1 cells compared with neocryptolepine. We further evaluated the activity of 8FNC against AGS cells in vitro . Our results indicate that 8FNC arrests the AGS cell cycle in the G2/M phase, reduces the mitochondrial membrane potential of AGS cells, and drives the initiation of apoptotic body formation in 8FNC-induced apoptosis. Moreover, 8FNC exhibits strong inhibitory effects on AGS cell migration. Studies on the molecular mechanisms of the cytotoxic activities of 8FNC revealed that it may play a significant role in the inhibitory effect on AGS human gastric cancer cells through the PI3K/AKT signaling pathway. In conclusion, 8FNC may become a promising lead compound in the development of potential clinical drug candidates for the treatment of gastric cancer.

In this work, small self-assembled messenger RNA nanospheres (mRNA-NSs) were successfully prepared by rolling circle transcription on a constructed apoptin plasmid. The self-assembled mRNA-NSs have a uniform diameter of approximately 65 nm, good dispersity in solution, and efficient therapeutic apoptin expression ability. In addition, the mRNA-NSs have a high loading capacity of 8.2% for the antitumor drug doxorubicin (Dox), which can effectively deliver the loaded Dox into 4 T1 cells. Cellular experiments show that Dox-loaded self-assembled messenger RNA nanospheres (mRNA-NSs@Dox) can reduce the viability of 4 T1 breast cancer cells by significantly upregulating Bax protein, thereby inducing the activation of Caspase 3 in 4 T1 cells. In vivo experiments show that mRNA-NSs@Dox can effectively increase the necrosis of tumor tissue, reduce the expression of Ki67, and exhibit a synergistic gene-chemotherapy effect in breast cancer-bearing mice. Taken together, this study successfully prepared self-assembled apoptin messenger RNA nanospheres (mRNA-NSs), which can improve the expression of the therapeutic protein apoptin and exhibit excellent synergistic antitumor effects after loading Dox, providing new ideas for the gene treatment and chemotherapy of breast cancer., 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 © 2021. Published by Elsevier Inc.)

Objective: Inhibition of tumor metastasis is a useful strategy to improve the efficacy of cancer therapy. Ventilagolin, a natural 1, 4-naphthoquinone derivative extracted from Ventilago leiocarpa Benth, has shown promising antitumor effects in previous studies. However, the effects and underlying mechanisms of Ventilagolin against migration, invasion and epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma (HCC) remain unclear. The present study has examined these effects and determined whether the proto-oncogene Pim-1 is involved., Methods: The effects of Ventilagolin on migration, invasion, Pim-1 and EMT-related proteins (eg, E-cadherin, N-cadherin, Vimentin) expression were assessed by scratch wound healing, Transwell, qRT-PCR and Western blot assays, respectively. Pim-1 stably overexpressed HepG2 and SMMC-7721 cells were generated to explore whether Ventilagolin inhibited migration, invasion and EMT of HCC cells via regulating Pim-1. Subcutaneous xenograft tumor model in nude mice was established. Histopathological changes of tumor tissues were examined by H&E staining and expressions of Pim-1 and EMT-related proteins were detected by immunohistochemistry., Results: Ventilagolin significantly ( P < 0.01) reduced the expression of Pim-1 levels in HepG2 and SMMC-7721 cells. Compared with the control group, the migration and invasion abilities of Pim-1-overexpressing HepG2 and SMMC-7721 cells were significantly ( P < 0.05, P < 0.01) enhanced, the expression of E-cadherin was decreased ( P < 0.01), and the levels of N-cadherin and Vimentin were upregulated ( P < 0.05, P < 0.01). Ventilagolin treatment effectively reversed these effects of Pim-1 overexpression. In vivo experiments showed that Ventilagolin could effectively suppress HCC tumor growth, downregulate Pim-1, N-cadherin and Vimentin expression, and upregulate E-cadherin expression., Conclusion: Ventilagolin suppresses HCC cell proliferation, migration and invasion and reverses EMT process by downregulating Pim-1, suggesting Ventilagolin is a potential therapeutic agent for treatment of HCC., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Liu et al.)

29 novel 20(S)-aminophosphonate derivatives of camptothecin were synthesized via a FeCl 3 - catalyzed one-pot reaction. All of these compounds displayed similar or superior cytotoxic activity in comparison with that of Irinotecan against Hep3B, MCF-7, A-549, MDA-MB-231, KB, and multidrug-resistant (MDR) KB-vin cell lines. Out of them, compound B07 exhibited significant cytotoxicity and 10-fold improvement in activity compared to Irinotecan. Mechanistically, B07 not only induced cell apoptosis and cell cycle arrest in Hep3B and MCF-7 cells, but also inhibited Topoisomerase I activity in the cell and cell-free system in a manner similar to that of Irinotecan. In both xenograft and primary HCC mouse models, B07 showed significant anti-tumor activity and was more potent than Irinotecan. Additionally, the acute toxicity assay showed that B07 had no apparent toxicity to the mouse liver, kidney, and hemopoietic system of the FVB/N mice. Therefore, these findings indicate that compound B07 could be a potential Topoisomerase I poison drug candidate for further clinical trial., (Copyright © 2021. Published by Elsevier Inc.)

Nanotechnology has recently become popular due to its potential for biomedical applications, especially for cancer treatment. Nanotechnology, featuring responsiveness to stimuli and stable drug release, has been widely used for the delivery of chemotherapeutic drugs, which are commonly used in the treatment of osteosarcoma. Smart stimuli-responsive nanotechnology is expected to improve the treatment of osteosarcoma. Herein, we focus on the latest research on nanomaterials in treating osteosarcoma that respond to internal and external stimuli. We also discuss nanocarriers with targeting ligands and the use of smart nanotechnology to partially reverse the multidrug resistance of osteosarcoma.

The inhalation administration method which has been applied to treat respiratory diseases has the characteristics of painlessness high efficiency and non-invasiveness, and the drug can also be targeted at the organ level first to reduce the loss of drug during circulation. Therefore, delivering medicine by inhalation administration has brought a new turnaround for lung cancer treatment. Herein from the perspective of combining traditional drug delivery design strategies with new drug delivery methods how to improve lung targeting efficiency and treatment efficacy is discussed. We also discuss the comparative advantages of inhaled drug delivery and traditional administration in the treatment of lung cancer such as intravenous injection. And the researches are divided into different forms of inhalation administration studied in the treatment of lung cancer in recent years, such as single-component loaded and multi-component loaded systems and their advantages. Finally, the obstacles of the application of carrier materials for inhalation administration and the prospects for improvement of lung cancer treatment methods are presented., (© 2021 IOP Publishing Ltd.)

Background: The efficacy of systemic chemotherapy for hepatocellular carcinoma (HCC) is predominantly hampered by low accumulation in tumor tissue and the high systemic toxicity of anticancer drugs. In this study, we designed an in situ drug-loaded injectable thermosensitive hydrogel system for the simultaneous delivery of norcantharidin-loaded nanoparticles (NCTD-NPs) and doxorubicin (Dox) via intratumoral administration to HCC tumors., Methods: NCTD-NPs were prepared by the thin film dispersion method using PCEC polymers as the carrier. Then, NCTD-NPs and Dox were co-encapsulated in a thermosensitive hydrogel based on Pluronic F127 (PF127) to construct a dual drug-loaded hydrogel system. The rheological properties of the drug-loaded hydrogel were studied using a rheometer. Drug release of the drug-loaded hydrogel and cytotoxicity in HepG2 cells were evaluated in vitro. An H22 tumor-bearing mice model was used to assess the in vivo antitumor activity of the drug-loaded hydrogel via intratumoral administration., Results: The prepared drug-loaded hydrogel exhibited good thermal-sensitive properties, which remained liquid at room temperature and rapidly transformed into a non-flowing gel at body temperature, and released the drugs in a sustained manner. In vitro studies revealed that the drug-loaded hydrogel exhibited remarkable antiproliferative activity in HepG2 cells compared to free drugs. In vivo antitumor efficacy experiments showed that the drug-loaded hydrogel significantly suppressed tumor growth, alleviated side effects, and prolonged the survival time of mice bearing H22 tumors compared to the other groups. Moreover, immunohistochemical staining revealed that the expression of Ki-67 and CD31 in the drug-loaded hydrogel group was significantly lower than that in the other groups (P < 0.05), indicating that the drug-loaded hydrogel effectively inhibited tumor proliferation and angiogenesis., Conclusion: The formulated hybrid thermosensitive hydrogel system with sustained drug release and enhanced therapeutic efficacy was demonstrated to be a promising strategy for the local-regional treatment of HCC via intratumoral administration., Competing Interests: The authors declare that they have no conflicts of interest related to this work., (© 2021 Gao et al.)

Aberrant activation of signal transducer and activator of transcription 3 (STAT3) plays a critical role in many types of cancers. As a result, STAT3 has been identified as a potential target for cancer therapy. In this study we identified 10,11-dehydrocurvularin (DCV), a natural-product macrolide derived from marine fungus, as a selective STAT3 inhibitor. We showed that DCV (2-8 μM) dose-dependently inhibited the proliferation, migration and invasion of human breast cancer cell lines MDA-MB-231 and MDA-MB-468, and induced cell apoptosis. In the two breast cancer cell lines, DCV selectively inhibited the phosphorylation of STAT3 Tyr-705, but did not affect the upstream components JAK1 and JAK2, as well as dephosphorylation of STAT3. Furthermore, DCV treatment strongly inhibited IFN-γ-induced STAT3 phosphorylation but had no significant effect on IFN-γ-induced STAT1 and STAT5 phosphorylation in the two breast cancer cell lines. We demonstrated that the α, β-unsaturated carbonyl moiety of DCV was essential for STAT3 inactivation. Cellular thermal shift assay (CETSA) further revealed the direct engagement of DCV with STAT3. In nude mice bearing breast cancer cell line MDA-MB-231 xenografts, treatment with DCV (30 mg·kg -1 ·d -1 , ip, for 14 days) markedly suppressed the tumor growth via inhibition of STAT3 activation without observed toxicity. Our results demonstrate that DCV acts as a selective STAT3 inhibitor for breast cancer intervention.

Synthetic polymersomes have structure similarity to bio-vesicles and could disassemble in response to stimuli for "on-demand" release of encapsulated cargos. Though widely applied as a drug delivery carrier, the burst release mode with structure complete destruction is usually taken for most responsive polymersomes, which would shorten the effective drug reaction time and impair the therapeutic effect. Inspired by the cell organelles' communication mode via regulating membrane permeability for transportation control, we highlight here a biomimetic polymersome with sustained drug release over a specific period of time via near-infrared (NIR) pre-activation. The polymersome is prepared by the self-assembling amphiphilic diblock copolymer P (OEGMA- co -EoS)- b -PNBOC and encapsulates the hypoxia-activated prodrug AQ4N and upconversion nanoparticle (PEG-UCNP) in its hydrophilic centric cavity. Thirty minutes of NIR pre-activation triggers cross-linking of NBOC and converts the permeability of the polymersome with sustained AQ4N release until 24 h after the NIR pre-activation. The photosensitizer EoS is activated and aggravates environmental hypoxic conditions during a sustained drug release period to boost the AQ4N therapeutic effect. The combination of sustained drug release with concurrent hypoxia intensification results in a highly efficient tumor therapeutic effect both intracellularly and in vivo . This biomimetic polymersome will provide an effective and universal tumor therapeutic approach.

Many artemisinin derivatives have good inhibitory effects on malignant tumors. In this work, a novel series of artemisinin derivatives containing piperazine and fluorine groups were designed and synthesized and their structures were confirmed by 1 H NMR, 13 C NMR and HRMS technologies. The in vitro cytotoxicity against various cancer cell lines was evaluated. Among the derivatives, compound 12h was found to exhibit not only the best activity against HCT-116 cells (IC 50  = 0.12 ± 0.05 μM), but also low toxicity against normal cell line L02 (IC 50  = 12.46 ± 0.10 μM). The mechanisms study revealed that compound 12h caused the cell cycle arrest in G1 phase, induced apoptosis in a concentration-dependent manner, significantly reduced mitochondrial membrane potential, increased intracellular ROS and Ca 2+ levels, up-regulated the expression of Bax, cleaved caspase-9, cleaved caspase-3, and down-regulated the expression of Bcl-2 protein. A series of analyses confirmed that 12h can inhibit HCT-116 cells migration and induce apoptosis by a mechanism of the mitochondria-mediated pathway in the HCT-116 cell line. The present work indicates that compound 12h may merit further investigation as a potential therapeutic agent for colorectal cancer., (Copyright © 2020. Published by Elsevier Inc.)

Purpose: A subset of pancreatic ductal adenocarcinomas (PDACs) is highly resistant to systemic chemotherapy, but no markers are available in clinical settings to identify this subset. We hypothesized that a glycan biomarker for PDACs called sialylated tumor-related antigen (sTRA) could be used for this purpose., Experimental Design: We tested for differences between PDACs classified by glycan expression in multiple systems: sets of cell lines, organoids, and isogenic cell lines; primary tumors; and blood plasma from human subjects., Results: The sTRA-expressing models tended to have stem-like gene expression and the capacity for mesenchymal differentiation, in contrast to the nonexpressing models. The sTRA cell lines also had significantly increased resistance to seven different chemotherapeutics commonly used against pancreatic cancer. Patients with primary tumors that were positive for a gene expression classifier for sTRA received no statistically significant benefit from adjuvant chemotherapy, in contrast to those negative for the signature. In another cohort, based on direct measurements of sTRA in tissue microarrays, the patients who were high in sTRA again had no statistically significant benefit from adjuvant chemotherapy. Furthermore, a blood plasma test for the sTRA glycan identified the PDACs that showed rapid relapse following neoadjuvant chemotherapy., Conclusions: This research demonstrates that a glycan biomarker could have value to detect chemotherapy-resistant PDAC in clinical settings. This capability could aid in the development of stratified treatment plans and facilitate biomarker-guided trials targeting resistant PDAC., (©2020 American Association for Cancer Research.)

Purpose: Cancer drug prescribing by medical oncologists accounts for the greatest variation in practice and the largest portion of spending on cancer care. We evaluated the association between a national commercial insurer's ongoing pay-for-performance (P4P) program for oncology and changes in the prescribing of evidence-based cancer drugs and spending., Methods: We conducted an observational difference-in-differences study using administrative claims data covering 6.7% of US adults. We leveraged the geographically staggered, time-varying rollout of the P4P program to simulate a stepped-wedge study design. We included patients age 18 years or older with breast, colon, or lung cancer who were prescribed cancer drug regimens by 1,867 participating oncologists between 2013 and 2017. The exposure was a time-varying dichotomous variable equal to 1 for patients who were prescribed a cancer drug regimen after the P4P program was offered. The primary outcome was whether a patient's drug regimen was a program-endorsed, evidence-based regimen. We also evaluated spending over a 6-month episode period., Results: The P4P program was associated with an increase in evidence-based regimen prescribing from 57.1% of patients in the preintervention period to 62.2% in the intervention period, for a difference of +5.1 percentage point (95% CI, 3.0 percentage points to 7.2 percentage points; P < .001). The P4P program was also associated with a differential $3,339 (95% CI, $1,121 to $5,557; P = .003) increase in cancer drug spending and a differential $253 (95% CI, $100 to $406; P = .001) increase in patient out-of-pocket spending, but no significant changes in total health care spending ($2,772; 95% CI, -$181 to $5,725; P = .07) over the 6-month episode period., Conclusion: P4P programs may be effective in increasing evidence-based cancer drug prescribing, but may not yield cost savings.

Combined administration of different drugs is a widely acknowledged approach for effective cancer therapy. However, the limited targeting, as well as inferior drug loading capacities of current drug delivery systems (DDS), are still the bottleneck for better performance in cancer treatment. Herein, we successfully developed a cancer cell membrane (CM) decorated calcium carbonate (CC) hybrid nanoparticles (HN) for the co-delivery of cisplatin (CDDP) and oleanolic acid (OA). The physicochemical property of HN/CDDP/OA was evaluated, which revealed that the as-prepared DDS was core-shell structured and well-dispersed nanoparticles with size around 100 nm. The HN/CDDP/OA showed high stability and biocompatibility with pH-responsive drug release. Moreover, the CM modification in HN also demonstrated highly elevated tumor-homing nature than bare CC. Finally, the feasibility of HN/CDDP/OA in the treatment of gastric cancer (MGC-803 cell line) was assessed. HN/CDDP/OA showed better performance than mono systems with enhanced apoptosis and capable of reversing multidrug resistance (MDR) of cancer cells.

Stimuli-responsive photodynamic therapy (PDT) is a hot topic in precise medicine, but the low abundance of responsive trigger molecules in early-stage disease limits application. Here we designed an amplifier with multiple upconversion luminances to achieve a near-infrared photo-switched cascade reaction triggered by specific microRNA and precise PDT of early-stage cancers. This amplifier was composed of photo-caged DNA nanocombs and an upconversion nanoparticle (UCNP) sensitized with IRDye 800CW. The nanocomb was prepared by assembling a photozipper-protected hairpin and two kinds of hybridizable hairpin probes on a DNA skeleton. Upon 808-nm light irradiation, the produced UV light cleaved off the photozipper to induce microRNA-responsive cascade hybridization reaction, activating the photosensitizers linked to different hairpins to generate reactive oxygen species (ROS) under the simultaneously emitted blue light for efficient PDT., (© 2020 Wiley-VCH GmbH.)

Compound 6 , a novel β-carboline comprising two 1-methyl-9 H -β-carboline-3-carboxylic acids and a biotin moiety conjugated together using tris(2-aminoethyl)amine, was synthesized and tested for its cytotoxicity toward MCF-7 and HepG2 cell lines and antitumor potency in an S180 tumor-bearing mouse model. Compound 6 was delivered via biotin receptor-mediated endocytosis and exerted its therapeutic effects by intercalation binding with DNA. In vivo antitumor evaluations of 6 revealed that it is efficacious and exhibits low systemic toxicity.

Due to the abnormal tumor vasculature and dense stroma, there is limited tumor perfusion in the immunosuppressive tumor microenvironment (TME). In order to reshape tumor blood vessels and enhance the penetration of anticancer drugs into the tumor tissue, an anionic liposome nanosystem with a "sandwich" structure was prepared. The chemotherapeutic agent topotecan (TPT) was encapsulated in the lipid hydrophilic layer, and the sensitizer indocyanine green (ICG) was loaded into the hydrophobic layer. In addition, the positively charged vascular normalization drug erlotinib (ERL) was adsorbed to the outermost layer of the microenvironment. The nanosystem showed superior tumor permeability in vitro / in vivo experiments compared with the ERL-treated group. The nanosystem entered the tumor through normalization of blood vessels after the action of ERL. Ultrasound treatment improves the vascular permeability, allowing the nanoparticles to penetrate blood vessels and reach tumor cells. Finally, in addition to cytotoxic effects, TPT can also down-regulate the expression of HIF-1α and so prolong the vascular normalization time. These experimental results showed that the nanosystem effectively improves the tumor microenvironment. This work indicates the great potential of vascular normalization combined with sonodynamic therapy and chemotherapy to enhance efficiency.

Cisplatin, as one of the most effective chemotherapeutic agents, its clinical use is limited by serious side effect of nephrotoxicity. Cisplatin-induced nephrotoxicity is closely related to apoptosis induction and activation of caspase. The present study aimed to explore the potential protective effect of ginsenoside Rk1 (Rk1), a rare ginsenoside generated during steaming ginseng, on cisplatin-induced nephrotoxicity and the underlying mechanisms in human embryonic kidney 293 (HEK-293) cells. Our results showed that the reduced cell viability induced by cisplatin could significantly recover by Rk1. Furthermore, glutathione (GSH) as an oxidative index, was elevated and the lipid peroxidation product malondialdehyde (MDA) was significantly decreased after Rk1 treatment compared to the cisplatin group. Additionally, Rk1 can also decrease the ROS fluorescence expression and increase the protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) compared to the cisplatin group, which suggested a suppression of oxidative response. More importantly, the cisplatin-induced elevated protein levels of Bax, cleaved caspase-3, cleaved caspase-9, and decreased protein level of Bcl-2 were reversed after treatment with Rk1. Our results elucidated the possible protective mechanism of Rk1 for the first time, which may involve in its anti-oxidation and anti-apoptosis effects., (© 2020 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

Multifunctional gold (Au)-based nanomaterials with high atomic number (symbol Z) and strong absorbance in the second near-infrared window (NIR-II) property are emerging as promising candidates for tumor thermo-radiotherapy. The main limitations of applying Au-based nanomaterials to biomedical studies include the absence of active tumor-targeting ability, penetrating efficiency, and stability. In this study, we present a novel type of tumor cell-derived stellate plasmonic exosomes (TDSP-Exos) for penetrative targeted tumor NIR-II thermo-radiotherapy and photoacoustic imaging. The TDSP-Exos are abundantly and easily produced by the incubation of tumor cells with gold nanostars, based on which gold nanostars promote the exocytosis of exosomes from tumor cells. Compared with bare gold nanostars, the TDSP-Exos exhibit pronounced accumulation in deep tumor tissues and perform well in both PA imaging and NIR-II thermo-radiotherapy against the tumor. Moreover, the TDSP-Exos improve tumor hypoxia to enhanced radiotherapy by NIR-II photothermal therapy. This work indicates that the tumor cell-derived exosomes have the potential to function as a universal carrier of photothermal agents for targeted tumor NIR-II thermo-radiotherapy.

Purpose: Cancer care has increasingly shifted from physician offices (MDOs) to hospital-based outpatient departments (HOPDs). This study compared the proportion of patients receiving optimal, evidence-based anticancer drug regimens and the cost of care when administered in these sites., Methods: Patients with breast, lung, or colorectal cancer were identified from a large health insurance database. Anticancer drug regimens were considered on pathway when they were on the payer's program list of optimal regimens when administered. Anticancer drug-related costs included all patient- and plan-paid costs on claims for anticancer drugs over the 6-month postindex period; total per-patient costs were summed over all claims in that period., Results: A total of 38,140 patients (MDO, n = 18,998; HOPD, n = 19,142) were included. On-pathway status was similar in HOPDs (59.5%; 95% CI, 58.6% to 60.4%) versus MDOs (60.8%; 95% CI, 59.8% to 61.8%; P = .069). HOPDs had substantially higher costs. Adjusted cancer drug-related costs were $63,763 (95% CI, $62,301 to $65,224) for HOPDs versus $36,500 (95% CI, $35,729 to $37,271) for MDOs ( P < .001); adjusted total costs were $115,843 (95% CI, $113,642 to $118,044) for HOPDs versus $77,346 (95% CI, $76,072 to $78,620) for MDOs ( P < .001). For Medicare Advantage, adjusted total costs were $61,812 for HOPDs compared with $62,769 for MDOs; adjusted drug-related costs were $31,610 for HOPDs compared with $33,168 for MDOs. For commercial insurance, total costs were $119,288 for HOPDs compared with $77,613 for MDOs; drug-related costs were $65,930 for HOPDs compared with $36,366 for MDOs., Conclusion: Total and cancer drug-related per-patient costs were higher in HOPDs versus MDOs, but on-pathway status was similar. The cost differential between HOPDs and MDOs was driven by commercially insured members rather than Medicare Advantage members.

The tumour microenvironment (TME) plays a pivotal role in tumour fate determination. The TME acts together with the genetic material of tumour cells to determine their initiation, metastasis and drug resistance. Stromal cells in the TME promote the growth and metastasis of tumour cells by secreting soluble molecules or exosomes. The abnormal microenvironment reduces immune surveillance and tumour killing. The TME causes low anti-tumour drug penetration and reactivity and high drug resistance. Tumour angiogenesis and microenvironmental hypoxia limit the drug concentration within the TME and enhance the stemness of tumour cells. Therefore, modifying the TME to effectively attack tumour cells could represent a comprehensive and effective anti-tumour strategy. Normal cells, such as stem cells and immune cells, can penetrate and disrupt the abnormal TME. Reconstruction of the TME with healthy cells is an exciting new direction for tumour treatment. We will elaborate on the mechanism of the TME to support tumours and the current cell therapies for targeting tumours and the TME-such as immune cell therapies, haematopoietic stem cell (HSC) transplantation therapies, mesenchymal stem cell (MSC) transfer and embryonic stem cell-based microenvironment therapies-to provide novel ideas for producing breakthroughs in tumour therapy strategies., (© 2020 The Authors. Cell Proliferation published by John Wiley & Sons Ltd.)

Colorectal cancer (CRC) is one of the major malignancies in humans. This study was designed to evaluate the effects of fucoidan on gut flora and tumor prevention in 1,2-dimethylhydrazine-induced colorectal carcinogenesis in rats. We found that dietary fucoidan treatment decreased the tumor incidence and mean tumor weight and increased cell apoptosis. Fucoidan treatment decreased the expression of β-catenin C-Myc, CyclinD1 and Survivin, while the Hippo pathway was activated with increased phosphorylation levels of mammalian sterile 20-like kinase 1 and 2, large tumor suppressor 1 and 2, and Yes-associated protein. Compared with the model group, the levels of interleukin (IL)-17 and IL-23 were decreased, but the levels of interferon-γ, IL-4 and IL-10 were increased, in the fucoidan group. Fucoidan treatment increased natural killer cells in peripheral blood and the proportion of CD4+ T cells. Immunofluorescence detection of colorectal tumor tissues showed decreased expression of Foxp3 and up-regulated expression of CD68 in the fucoidan group. Moreover, fucoidan treatment decreased the levels of diamine oxidase and lipopolysaccharides and up-regulated the levels of tight junction proteins. 16S rDNA high-throughput sequencing revealed that fucoidan treatment decreased the abundance of Prevotella and increased the abundance of Alloprevotella. Fucoidan increased the levels of butyric acid and valeric acid compared to the model group. This study provides experimental evidence that dietary fucoidan may prevent colorectal tumorigenesis by regulating gut microecology and body immunity. Meanwhile, fucoidan activated the Hippo pathway and down-regulated the β-catenin pathway to induce tumor cell apoptosis and suppress tumor growth., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Polyphyllin I (PPI), a bioactive constituent extracted from the rhizomes of Paris polyphylla, is cytotoxic to several cancer types. This study was designed to explore whether PPI prevents non-small-cell lung cancer (NSCLC) growth and to investigate the molecular mechanism. AMP-activated protein kinase (AMPK) has been implicated in the activation of autophagy in distinct tissues. In cultured human NSCLC cell lines, PPI induces autophagy by activating AMPK and then inhibiting mTOR signaling in a concentration-dependent manner. Furthermore, the activation of autophagy induced by PPI was reversed by the AMPK inhibitor compound C. Computational docking showed that PPI directly interacted with the allosteric drug and metabolite site of AMPK to stabilize its activation. Microscale thermophoresis and Drug Affinity Responsive Targeting Stability (DARTS) assay further confirmed the high affinity between PPI and AMPK. In vivo studies indicated that PPI suppressed the growth of NSCLC and increased the levels of LC3-II and phosphorylated AMPK in tumors isolated from a xenograft model of NSCLC in mice. Moreover, PPI exhibited favorable pharmacokinetics in rats. In summary, PPI conclusively acts as a direct AMPK activator to induce cell autophagy which inhibits the growth of NSCLC cells. In the future, PPI therapy should be applied to treat patients with NSCLC., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

As part of continuing our research on diverse C-7 derivatives of camptothecin (CPT), 16 CPT derivatives bearing piperazinyl-thiourea chemical scaffold and different substituent groups have been designed, synthesized and evaluated in vitro for cytotoxicity against five tumor cell lines (A-549, MDA-MB-231, MCF-7, KB and KBvin). As a result, all the synthesized compounds showed promising in vitro cytotoxic activity against the five tumor cell lines tested, and were more potent than irinotecan. Importantly, compounds 13 g (IC 50 = 0.514 μM) and 13o (IC 50 = 0.275 μM) possessed similar or better antiproliferative activity against the multidrug-resistant (MDR) KBvin subline than that of topotecan (IC 50 = 0.511 μM) and merit further development as anticancer candidates for clinical trail. With these results in hand, we have a reason to conclude that incorporating piperazinyl-thiourea motifs into position-7 of camptothecin confers well cytotoxic activity against cancer cell lines, probably resulting in new anticancer drugs.

Sorafenib resistance is a major challenge in the therapy for advanced hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of HCC resistance to sorafenib remain unclear. Activator of thyroid and retinoid receptor (ACTR, also known as SRC-3), overexpressed in HCC patients, plays an important oncogenic role in HCC; however, the link between ACTR and sorafenib resistance in HCC is unknown. Our study demonstrated that ACTR was one of the most upregulated genes in sorafenib-resistant HCC xenografts. ACTR increases sorafenib resistance through regulation of the Warburg effect. ACTR promotes glycolysis through upregulation of glucose uptake, ATP and lactate production, and reduction of the extracellular acidification and the oxygen consumption rates. Glycolysis regulated by ACTR is vital for the susceptibility of HCC to sorafenib in vitro and in vivo. Mechanistically, ACTR knockout or knockdown decreases the expression of glycolytic enzymes. In HCC patients, ACTR expression is positively correlated with glycolytic gene expression and is associated with poorer outcome. Furthermore, ACTR interacts with the central regulator of the Warburg effect, c-Myc, and promotes its recruitment to glycolytic gene promoters. Our findings provide new clues regarding the role of ACTR as a prospective sensitizing target for sorafenib therapy in HCC., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)