antimony-potassium-tartrate and Neoplasms

cis-Diamminedichloroplatinum/cisplatin (CDDP) is a major drug used in cancer chemotherapy; however, the toxic side-effects and development of drug resistance represent major challenges to the clinical use of CDDP. The aim of the present study was to identify effective drug combination regimens through high-throughput drug screening that can enhance the efficacy of CDDP, and to investigate the underlying mechanisms. A cell-based high-throughput screening methodology was implemented, using a library of 1,280 Food and Drug Administration (FDA)-approved drugs, to identify clinical compounds that act synergistically with CDDP. Our study identified two compounds, namely potassium antimony tartrate and topotecan, that significantly enhanced the sensitivity of colorectal and non-small cell lung cancer cells to CDDP. The synergistic action of both compounds with CDDP was confirmed by further quantitative analyses. Topotecan is a topoisomerase-1 inhibitor that has previously been shown to enhance the clinical response and overall patient survival when combined with CDDP by a yet unclear mechanism. We demonstrated that the combination of topotecan with CDDP significantly inhibited colony formation ability and increased the apoptosis of several cancer cell lines. Mechanistic analyses revealed that topotecan enhanced CDDP-induced DNA damage and inhibited the repair of DNA strand breaks, without affecting the cellular platinum content. Overall, the findings of this study demonstrated that the use of the FDA-approved drug panel in high-throughput screening is an effective method for identifying effective therapeutic regimens that are clinically relevant, and may have high feasibility for translation into clinical practice.

Topics: Antimony Potassium Tartrate; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cisplatin; Drug Screening Assays, Antitumor; Drug Synergism; High-Throughput Screening Assays; Humans; Neoplasms; Topotecan; Tumor Cells, Cultured

Topics: Antimony Potassium Tartrate; Antineoplastic Agents; Carcinoma, Small Cell; Drug Screening Assays, Antitumor; History, 16th Century; History, 17th Century; History, 18th Century; History, 19th Century; History, 20th Century; History, Ancient; Humans; Lung Neoplasms; Neoplasms; Tumor Cells, Cultured

Cross-resistance between cisplatin (DDP) and metalloid salts in human cells was sought on the basis that mechanisms that mediate metalloid salt cross-resistance in prokaryotes are evolutionarily conserved. Two ovarian and two head and neck carcinoma cell lines selected for DDP resistance were found to be cross-resistant to antimony potassium tartrate, which contains trivalent antimony. The DDP-resistant variant 2008/A was also cross-resistant to arsenite but not to stibogluconate, which contains pentavalent antimony. A variant selected for resistance to antimony potassium tartrate was cross-resistant to DDP and arsenite. Resistance to antimony potassium tartrate and arsenite was of a similar magnitude (3-7-fold), whereas the level of resistance to DDP was greater (17-fold), irrespective of whether the cells were selected by exposure to DDP or to antimony potassium tartrate. In the resistant sublines, uptake of [3H]-dichloro(ethylenediamine) platinum(II) was reduced to 41-52% of control, and a similar deficit was observed in the accumulation of arsenite. We conclude that DDP, antimony potassium tartrate, and arsenite all share a common mechanism of resistance in human cells and that this is due in part to an accumulation defect.

Topics: Anions; Antimony Potassium Tartrate; Arsenites; Biological Transport; Carcinoma; Cisplatin; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Female; Head and Neck Neoplasms; Humans; Neoplasms; Organoplatinum Compounds; Ovarian Neoplasms; Selection, Genetic; Tumor Cells, Cultured