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Oxaliplatin‐induced peripheral neuropathy (OIPN) is a common and dose‐limiting toxic effect that markedly limits the use of oxaliplatin and affects the quality of life. Although it is common, the underlying mechanisms of OIPN remain ambiguous. Recent studies have shown that the platinum accumulation in peripheral nervous system, especially in dorsal root ganglion, is a significant mechanism of OIPN. Several specific transporters, including organic cation transporters, high‐affinity copper uptake protein1 (CTR1), ATPase copper transporting alpha (ATP7A) and multidrug and toxin extrusion protein 1 (MATE1), could be associated with this mechanism. This review summarizes the current research progress about the relationship between platinum accumulation and OIPN, as well as suggests trend for the future research. [ABSTRACT FROM AUTHOR]

Enhancer of zeste homolog 2 (EZH2), which is overexpressed in a wide range of tumors, contributes to ovarian cancer malignancy in several different ways. We aimed to illustrate the role of EZH2 in ovarian cancer cisplatin resistance and to identify possible underlying mechanisms of this role that may provide a rationale for targeting EZH2 in cancer treatment. Here, we present data indicating that EZH2 overexpression is associated with cisplatin resistance and intracellular platinum drug accumulation. Measurements of EZH2 in 84 ovarian cancer patients suggested that patients with high EZH2 levels tend to have poor responses to cisplatin. The EZH2 level progressively increased in cells receiving repeated cisplatin exposure. Downregulation of EZH2 not only sensitized cellular reactions to cisplatin and increased cellular platinum accumulation when cells were exposed to both cisplatin and BODIPY‐Pt (a fluorescent cisplatin complex) but also protected copper transporter 1, a high‐affinity copper transporter closely related to cisplatin resistance, from cisplatin‐induced proteasomal degradation. Overall, these findings identify a new mechanism that expands the unrecognized role of EZH2 in ovarian cancer cisplatin resistance. [ABSTRACT FROM AUTHOR]

The therapeutic efficacy of the anticancer drug cisplatin is limited by the development of resistance. We therefore investigated newly synthesized platinum-nitroxyl complexes (PNCs) for their potential to circumvent cisplatin resistance. The complexes used were PNCs with bivalent cis-Pt(RNH)(NH)Cl and cis-Pt(DAPO)Ox and four-valent platinum cis, trans, cis-Pt(RNH)(NH)(OR)Cl and cis, trans, cis-Pt(DAPO)(OR)Ox, where R are TEMPO or proxyl nitroxyl radicals, DAPO is trans-3,4-diamino-2,2,6,6-tetramethylpiperidine-1-oxyl, and OR and Ox are carboxylato and oxalato ligands, respectively. The complexes were characterized by spectroscopic methods, HPLC, log P data and elemental analysis. We studied intracellular platinum accumulation, DNA platination and cytotoxicity upon treatment with the PNCs in a model system of the bladder cancer cell line RT112 and its cisplatin-resistant subline RT112-CP. Platinum accumulation and DNA platination were similar in RT112 and RT112-CP cells for both bivalent and four-valent PNCs, in contrast to cisplatin for which a reduction in intracellular accumulation and DNA platination was observed in the resistant subline. The PNCs were found to platinate DNA in relation to the length of their axial RO-ligands. Furthermore, the PNCs were increasingly toxic in relation to the elongation of their axial RO-ligands, with similar toxicities in RT112 and its cisplatin-resistant subline. Using a cell-free assay, we observed induction of oxidative DNA damage by cisplatin but not PNCs suggesting that cisplatin exerts its toxic action by platination and oxidative DNA damage, while cells treated with PNCs are protected against oxidatively induced lesions. Altogether, our study suggests that PNCs may provide a more effective treatment for tumors which have developed resistance toward cisplatin. [ABSTRACT FROM AUTHOR]

To assess the potential cytostatic properties of Pt(II) complexes with 3-hydroxymethylpyridine (3-hmpy) as the only carrier ligand, novel cis -[PtCl 2 (3-hmpy) 2 ] ( 1 ) and trans -[PtCl 2 (3-hmpy) 2 ] ( 2 ) have been prepared. Elemental analysis, FTIR spectroscopy, multinuclear NMR spectroscopy and X-ray crystallography were used to determine their structures. Based on the results obtained with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and clonogenic assay on T24 human bladder carcinoma cells (T24), the most potent compound 2 was further tested for cytotoxicity in human ovarian carcinoma cell lines - cisplatin sensitive (IGROV 1) and its resistant subclone (IGROV 1/RDDP). The cytotoxicity of compound 2 in IGROV 1/RDDP is comparable to cisplatin. Furthermore, compound 2 induced severe conformational changes in plasmid DNA, which resulted in a delayed onset of apoptosis in T24 cells, and higher amounts of Pt in tumours and serum compared to cisplatin. In addition, in vivo antitumour effectiveness was comparable to that of cisplatin with a smaller reduction of animals' body weight, thus demonstrating that it is a promising transplatin analogue which deserves further studies. [ABSTRACT FROM AUTHOR]

Background: Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death in the USA. Recurrence rates are high after front-line therapy and most patients eventually die from platinum (Pt) - resistant disease. Cisplatin resistance is associated with increased nucleotide excision repair (NER), decreased mismatch repair (MMR) and decreased platinum uptake. The objective of this study is to investigate how a novel combination of sodium arsenite (NaAsO2) and hyperthermia (43°C) affect mechanisms of cisplatin resistance in ovarian cancer. Methods: We established a murine model of metastatic EOC by intraperitoneal injection of A2780/CP70 human ovarian cancer cells into nude mice. We developed a murine hyperthermic intraperitoneal chemotherapy model to treat the mice. Mice with peritoneal metastasis were perfused for 1 h with 3 mg/kg cisplatin ± 26 mg/kg NaAsO2 at 37 or 43°C. Tumors and tissues were collected at 0 and 24 h after treatment. Results: Western blot analysis of p53 and key NER proteins (ERCC1, XPC and XPA) and MMR protein (MSH2) suggested that cisplatin induced p53, XPC and XPA and suppressed MSH2 consistent with resistant phenotype. Hyperthermia suppressed cisplatin-induced XPC and prevented the induction of XPA by cisplatin, but it had no effect on Pt uptake or retention in tumors. NaAsO2 prevented XPC induction by cisplatin; it maintained higher levels of MSH2 in tumors and enhanced initial accumulation of Pt in tumors. Combined NaAsO2 and hyperthermia decreased cisplatin-induced XPC 24 h after perfusion, maintained higher levels of MSH2 in tumors and significantly increased initial accumulation of Pt in tumors. ERCC1 levels were generally low except for NaAsO2 co-treatment with cisplatin. Systemic Pt and arsenic accumulation for all treatment conditions were in the order: kidney > liver = spleen > heart > brain and liver > kidney = spleen > heart > brain respectively. Metal levels generally decreased in systemic tissues within 24 h after treatment. Conclusion: NaAsO2 and/or hyperthermia have the potential to sensitize tumors to cisplatin by inhibiting NER, maintaining functional MMR and enhancing tumor platinum uptake. [ABSTRACT FROM AUTHOR]

Abstract: A new anticancer-active platinum(II) compound [Pt(A9pyp)(dmso)(cbdca)], containing the E-1-(9-anthryl)-3-(2-pyridyl)-2-propenone ligand (abbreviated as A9pyp) has been synthesized by the replacement of the anionic chloride ligands in cis-[Pt(A9pyp)(dmso)Cl2] by the dianionic chelating cyclobutanedicarboxylate ligand (abbreviated as cbdca). The in vitro relevance of the leaving group of these new platinum(II) compounds has been investigated. Measurements of the time-dependent intracellular accumulation of both compounds in human ovarian carcinoma cell lines show that the leaving group affects their cellular uptake. In addition, the leaving group also influences DNA platination, and, therefore, has an effect on the biological activity against a pair of human ovarian carcinoma cell lines, i.e. sensitive and resistant to cisplatin. [Copyright &y& Elsevier]

Abstract: The anticancer properties of two new fluorescent platinum(II) compounds, cis-[Pt(A9opy)Cl2] and cis-[Pt(A9pyp)(dmso)Cl2] are described. These compounds are highly active against several human tumor cell lines, including human ovarian carcinoma sensitive and cisplatin-resistant cell lines (A2780 and A2780R). To study the cellular processing of these new compounds, a series of in vitro studies have been performed, including the investigation of intracellular platinum accumulation and DNA-platination experiments in A2780 and A2780R cells. Compared to cisplatin, both compounds are accumulated highly in both sensitive and resistant cell lines, and more platinum has been found to bind to the nuclear DNA. Interestingly, cis-[Pt(A9opy)Cl2] shows high accumulation and DNA adduct formation in the resistant cell line A2780R, as compared to the sensitive counterpart A2780 cell line. This suggests that cis-[Pt(A9opy)Cl2] is able to overcome some of the well-known resistance mechanisms in this cell line, such as decreased cellular uptake and increased DNA repair. [Copyright &y& Elsevier]

Abstract: Transplatinum planaramine complexes with carboxylate ligands as leaving groups, trans-[Pt(O2CR)2(L)(L′)] (L=L′=pyridine; L=NH3, L′=pyridine, isoquinoline, thiazole, quinoline, etc.), are potential anticancer complexes with cytotoxicity in some cases equivalent to that of cisplatin. The carboxylate complexes are, as a family, very water-soluble and surprisingly stable towards hydrolysis – resembling carboplatin in their reactivity. Their pharmacological properties can be systematically modified by steric and electronic effects of the donor groups as well as in the leaving carboxylate ligands. Previously, we have recognized the leaving group formate as having appropriate kinetics for bioligand substitution . In this paper we directly compared the effect on biological properties of a pyridine versus isoquinoline-based carrier group. Binding to calf thymus DNA was similar for both compounds but the distortions produced on DNA, as assessed by T m (melting temperature) and an ethidium bromide fluorescence reporter assay, were more marked for the isoquinoline ligand. Model studies with 5′-GMP (5′-guanosinemonophosphate) confirmed these trends, with the product trans-[Pt(5′-GMP)2(NH3)(isoquinoline)] showing evidence of restricted rotation caused by steric hinderance of three rigid planar rings on the central platinum. A cross-linking assay on pUC19 plasmid confirmed a higher % of interstrand adducts for the isoquinoline compound. This “enhanced” reactivity was matched by higher cytotoxicity in HCT116 human colon tumor cells, and also with enhanced cellular accumulation. Thus, a combination of systematic biophysical and biological studies indicates that trans-[Pt(O2CH)2(NH3)(isoquinoline)] has the most promising range of chemical and biological properties for further development and examination. [Copyright &y& Elsevier]

Abstract: Oxaliplatin is used for treatment of colon cancer in combination with 5-fluorouracil or irinotecan. Oxaliplatin has similar, but also different resistant mechanisms as cisplatin. We studied the activity of oxaliplatin in ovarian and colon cancer cells with different resistance patterns to cisplatin. The 40-fold cisplatin-resistant cell line ADDP was only 7.5-fold resistant to oxaliplatin. The gemcitabine-resistant AG6000 cell line, 9-fold resistant to cisplatin, was not cross-resistant. LoVo-175X2, with mutant p53 showed no resistance compared to the empty vector control. However, LoVo-Li, with inactive p53, was 3.6-fold resistant corresponding to decreased accumulation and Pt adducts. Accumulation and DNA adducts formation showed no significant correlation with oxaliplatin sensitivity. Cell cycle distribution after exposure to oxaliplatin showed arrest in G2/M (A2780) or in S-phase (LoVo-92) for wt-p53 cells. ADDP and LoVo-Li showed G1 arrest followed by S-phase arrest and no changes in distribution, respectively. The cell cycle related proteins Cyclins A and B1 and (p)CDC25C were marginally affected by oxaliplatin. Expression of hCTR1 was decreased in ADDP, LoVo-Li and AG6000, OCT1 decreased in ADDP and AG6000 and OCT3 in LoVo-175X2, compared to the parental cell lines. In ADDP and LoVo-175X2 ATP7A and B were decreased but were increased in AG6000. From this study it can be concluded that changes in cell cycle distribution were cell line dependent and not related to changes in expression of Cyclin A or B1. Oxaliplatin accumulation was related to hCTR1 and, at low concentration, ATP7A to DNA adducts formation while the retention was related to hCTR1, OCT2 and ATP7B. [Copyright &y& Elsevier]

Oxaliplatin (OHP) treatment of colorectal cancer (CRC) frequently leads to resistance. OHP resistance was induced in CRC cell lines LoVo-92 and LoVo-Li and a platinum-sensitive ovarian cancer cell line, A2780, and related to cellular platinum accumulation, platinum-DNA adducts, transporter expression, DNA repair genes, gene expression arrays, and array-CGH profiling. Pulse (4 h, 4OHP) and continuous exposure (72 h, cOHP) resulted in 4.0 to 7.9-fold and 5.0 to 11.8-fold drug resistance, respectively. Cellular oxaliplatin accumulation and DNA-adduct formation were decreased and related to OCT1-3 and ATP7A expression. Gene expression profiling and pathway analysis showed significantly altered p53 signaling, xenobiotic metabolism, role of BRCA1 in DNA damage response, and aryl hydrocarbon receptor signaling pathways, were related to decreased ALDH1L2, Bax, and BBC3 (PUMA) and increased aldo-keto reductases C1 and C3. The array-CGH profiles showed focal aberrations. In conclusion, OHP resistance was correlated with total platinum accumulation and OCT1-3 expression, decreased proapoptotic, and increased anti-apoptosis and homologous repair genes. [ABSTRACT FROM AUTHOR]