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Pyruvate kinase 2 (PKM2) and pyruvate dehydrogenase kinase 1 (PDK1) are two key enzymes in tumor glucose metabolism pathway that not only promote tumor growth and proliferation through accelerating aerobic glycolysis, but also contribute to drug resistance of non-small cell lung cancer (NSCLC). Considering that targeting PKM2 or PDK1 alone seems insufficient to remodel abnormal glucose metabolism to achieve significant antitumor activity, we proposed a "two-step approach" that regulates PKM2 and PDK1 synchronously. Firstly, we found that the combination of ML265 (PKM2 activator) and AZD7545 (PDK1 inhibitor) could synergistically inhibit proliferation and induce apoptosis in H1299 cells. Base on this, we designed a series of novel shikonin (SK) thioether derivatives as PKM2/PDK1 dual-target agents, among which the most potent compound E5 featuring a 2-methyl substitution on the benzene ring exerted significantly increased inhibitory activity toward EGFR mutant NSCLC cell H1975 (IC 50  = 1.51 μmol/L), which was 3 and 17-fold more active than the lead compound SK (IC 50  = 4.56 μmol/L) and the positive control gefitinib (IC 50  = 25.56 μmol/L), respectively. Additionally, E5 also showed good anti-tumor activity in xenografted mouse models, with significantly lower toxicity side effects than SK. Moreover, E5 also inhibited the entry of PKM2 into nucleus to regulate the transcriptional activation of oncogenes, thus restoring the sensitivity of H1975 cell to gefitinib. Collectively, these data demonstrate that E5, a dual inhibitor of PKM2/PDK1, may be a promising adjunct to gefitinib in the treatment of EGFR-TKIs resistant NSCLC, deserving further investigation., 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.)

Introduction: Paclitaxel is a powerful and effective anti-tumor drug with wide clinical application. However, there are still some limitations, including poor water solubility, low specificity, and susceptibility to drug resistance. The peptide-drug conjugates (PDCs) represent a rising class of therapeutic drugs, which combines small-molecule chemotherapeutic drugs with highly flexible peptides through a cleavable or non-cleavable linker. When this strategy is applied, the therapeutic effects of paclitaxel can be improved., Areas Covered: In this review, we discuss the application of the PDCs strategy in paclitaxel, including two parts: the tumor targeting peptide-paclitaxel conjugates and the cell penetrating peptide-paclitaxel conjugates., Expert Opinion: Combining drugs with multifunctional peptides covalently is an effective strategy for delivering paclitaxel to tumors. Depending on different functional peptides, conjugates can increase the water solubility of paclitaxel, tumor permeability of paclitaxel, the accumulation of paclitaxel in tumor tissues, and enhance the antitumor effect of paclitaxel. In addition, due to the change of cell entry mechanism, partial conjugates can restore the therapeutic activity of paclitaxel against resistant tumors. Notably, in order to better translate into the clinical field in the future, more research should be conducted to ensure the safety and effectiveness of peptide-paclitaxel conjugates.

Background: The efficacy of a traditional anticancer drug is challenged by adverse effects of the drug, including its nonspecific bio-distribution, short half-life, and side effects. Dendrimer-based targeted drug delivery system has been considered a promising strategy to increase targeting ability and reduce adverse effects of anti-cancer drugs., Objective: This study analyzed the feasibility of whether the anticancer drug 5-fluorouracil (5-FU) could be delivered by functionalized fifth-poly(amidoamine) (PAMAM) with the peptide WP05 and the acetic anhydride to the liver cancer cells, reducing the toxicity of the PAMAM and improving the targeting property of 5-FU during delivery., Methods: The functionalized PAMAM-based nanoformulation (WP05-G5.0NHAC-FUA) was fabricated through an amide condensation reaction to improve the therapeutic efficacy of 5-Fluorouracil (5-FU) in hepatocellular carcinoma (HCC). The physicochemical structure, particle size, zeta potential, stability, and in vitro release characteristics of WP05-G5.0NHAC-FUA were evaluated. In addition, the targeting, biocompatibility, anti-proliferation, and anti-migration of WP05-G5.0NHAC-FUA were investigated. The anti-tumor effect of WP05-G5.0NHAC-FUA in vivo was evaluated by constructing xenograft tumor models of human hepatoma cells (Bel-7402) implanted in nude mice., Results: The resultant WP05-G5.0NHAC-FUA displayed spherical-like nanoparticles with a size of 174.20 ± 3.59 nm. Zeta potential and the drug loading of WP05-G5.0NHAC-FUA were 5.62 ± 0.41mV and 28.67 ± 1.25%, respectively. Notably, the optimized 5-FU-loaded formulation showed greater cytotoxicity with an IC 50 of 30.80 ± 4.04 μg/mL than free 5-FU (114.93 ± 1.43 μg/mL) in Bel-7402 cancer liver cells, but a significantly reduced side effect relative to free 5-FU in L02 normal liver cells. In vivo animal study further confirmed efficient tumor accumulation and enhanced therapeutic efficiency., Conclusion: The developed nanoformulation is a promising platform for the targeting delivery of 5-FU and provides a promising solution for improving the efficacy of hepatocellular carcinoma chemotherapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Undesirable intracellular vesicular compartmentalization of anticancer drugs in cancer cells is a common cause of chemoresistance. Strategies aimed at circumventing this problem may improve chemotherapeutic efficacy. We report a novel photophysical strategy for controlled-disruption of vesicular sequestration of the anticancer drug doxorubicin (DOX). Single-walled carbon nanotubes (SWCNTs), modified with folate, were trapped in acidic vesicles after entering lung cancer cells. Upon irradiation by near-infrared pulsed laser, these vesicles were massively broken by the resulting photoacoustic shockwave, and the vesicle-sequestered contents were released, leading to redistribution of DOX from cytoplasm to the target-containing nucleus. Redistribution resulted in 12-fold decrease of the EC50 of DOX in lung cancer cells, and enhanced antitumor efficacy of low-dose DOX in tumor-bearing mice. Side effects were not observed. These findings provide insights of using nanotechnology to improve cancer chemotherapy, i.e. not only for drug delivery, but also for overcoming intracellular drug-transport hurdles.

RAD51 recombinase plays a critical role for cancer cell proliferation and survival. Targeting RAD51 is therefore an attractive strategy for treating difficult-to-treat cancers, e.g. triple negative breast cancers which are often resistant to existing therapeutics. To this end, we have designed, synthesized and evaluated a panel of new RAD51 inhibitors, denoted IBR compounds. Among these compounds, we have identified a novel small molecule RAD51 inhibitor, IBR120, which exhibited a 4.8-fold improved growth inhibition activity in triple negative human breast cancer cell line MBA-MD-468. IBR120 also inhibited the proliferation of a broad spectrum of other cancer cell types. Approximately 10-fold difference between the IC50 values in normal and cancer cells were observed. Moreover, IBR120 was capable of disrupting RAD51 multimerization, impairing homologous recombination repair, and inducing apoptotic cell death. Therefore, these novel RAD51 inhibitors may serve as potential candidates for the development of pharmaceutical strategies against difficult-to-treat cancers., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Several studies have shown that the interaction of CXC chemokine receptor 4 (CXCR4) with its ligand, stromal cell-derived factor-1alpha (SDF-1alpha) is closely involved in the directional migration of some tumors toward specific organs, which provides a new pathway against cancer metastasis. We previously developed an alpha-helix-defective mutant of SDF-1alpha, SDF-1/54 that displays obvious antagonistic activity to CXCR4. But it is necessary to ensure the targeting of SDF-1/54 to tumors in vivo since many normal tissues also express CXCR4. It is known that most tumor cells highly express epidermal growth factor receptor (EGFR). Meanwhile, decorin (DCN), a specific antagonist of EGFR, can target the tumor cells enriched in EGFR and cause a significant downregulation of EGFR. Hereby, we further generated a fusion construct of SDF-1/54 and DCN to expect to enhance the targeting of SDF-1/54 to tumors by dual blocking effects on CXCR4 and EGFR. This study focused on expression of recombinant chimera SDF-1/54-DCN in Escherichia coli, purification and bioactivity to inhibit the physiological functions mediated by CXCR4 and EGFR respectively in various tumor cell lines in vitro. Results indicated that SDF-1/54-DCN could inhibit both chemotaxis and proliferation of the tumor cells we used, which may be attributed to its blocking to CXCR4 and EGFR. These findings suggest that this strategy to link SDF-1/54 with DCN may be a promising approach to increase the targeting of SDF-1/54 to the tumors coexpressing CXCR4 and EGFR.

Decorin (DCN) is a member of the small leucine-rich proteoglycan gene family. Many studies indicated that DCN inhibited fibrosis and scar-formation by neutralization of TGF-P and interfering the binding of TGF-beta with its receptor, which induced ectopic deposition of extracellular matrix. Additionally, DCN can prevent the proliferation and metastasis of tumor cells by activating EGFR/MAPK/p21 signal pathway and inhibiting the cell proliferation pathway mediated by EGF-EGFR. It is suggested that the recombinant DCN had potential pharmaceutical potency in treatment of chronic fibrosis and neoplasm for its critical biological activities and low immunogenicity.

RAD51 recombinase plays a critical role for cancer cell proliferation and survival. Targeting RAD51 is therefore an attractive strategy for treating difficult-to-treat cancers, e.g. triple negative breast cancers which are often resistant to existing therapeutics. To this end, we have designed, synthesized and evaluated a panel of new RAD51 inhibitors, denoted IBR compounds. Among these compounds, we have identified a novel small molecule RAD51 inhibitor, IBR120, which exhibited a 4.8-fold improved growth inhibition activity in triple negative human breast cancer cell line MBA-MD-468. IBR120 also inhibited the proliferation of a broad spectrum of other cancer cell types. Approximately 10-fold difference between the IC50 values in normal and cancer cells were observed. Moreover, IBR120 was capable of disrupting RAD51 multimerization, impairing homologous recombination repair, and inducing apoptotic cell death. Therefore, these novel RAD51 inhibitors may serve as potential candidates for the development of pharmaceutical strategies against difficult-to-treat cancers.

Three oxovanadium complexes incorporating thiosemicarbazones and fluoro-phenanthroline derivatives [VO(hntdtsc)(CF 3 PIP)] ( 1 ) (hntdtsc = 2-hydroxyl-1-naphthaldehyde thiosemicarbazone, CF 3 PIP = 2-(2-trifluoromethyl phenyl)imidazole[4,5-f][1,10]phenanthroline [VO(hntdtsc)( m -CF 3 PIP)] ( 2 ) ( m -CF 3 PIP = 2-(3-trifluoromethyl phenyl)imidazole[4,5-f][1,10]phenanthroline), [VO(hntdtsc)( p -CF 3 PIP)] ( 3 ) ( p -CF 3 PIP = 2-(4-trifluoromethyl phenyl)imidazole[4,5-f][1,10]phenanthroline) were newly synthesized and characterized by elemental analysis and spectroscopic techniques. Their interactions with calf-thymus DNA (CT-DNA) and photocleavage properties with plasmid pBR322 DNA were investigated by a host of analytical methods. The results suggest that these three complexes interact with CT-DNA through an non-classical intercalative mode and can efficiently cleavage plasmid pBR322 DNA upon exposure to ultraviolet light. In addition, they all exhibited considerable anti-proliferative activity in vitro against human Hela, CaSki, SiHa, ECa9706, ECa109, MDA-MB-231 and MCF-7 tumor cell lines, to have an IC 50 values for cytotoxicity in the low micromole range 0.31–6.15 μM, which is very close to that of cisplatin (0.52–2.49 μM). Furthermore, their antitumor mechanism has been analyzed by the cell cycle arrest, and apoptosis analysis. The results showed that complexes 2 and 3 caused G0/G1 phase arrest in ECa9706 cells, but differentiatedly induced G0/G1 and S phase arrest in ECa109 cells. And significant apoptosis were observed in both the two tumor cell lines, which indicate these oxovanadium complexes induce proliferative suppression of ECa9706 and ECa109 cells via the induction of apoptosis. [ABSTRACT FROM AUTHOR]