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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Antineoplastic Agents, Cation Transport Proteins, Cell Line, Tumor, Cell Proliferation, Cell Survival, Cisplatin, DNA Adducts, Dichlororibofuranosylbenzimidazole, Dose-Response Relationship, Drug, Drug Synergism, Emodin, Female, Humans, Inhibitory Concentration 50, Intracellular Space, Nucleic Acid Synthesis Inhibitors, Ovarian Neoplasms, Protein Kinase Inhibitors, RNA Interference, Spectrophotometry, Atomic, Time Factors.
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Do protein kinase inhibitors emodin and dichloro-ribofuranosylbenzimidazole modulate the cellular accumulation and cytotoxicity of cisplatin in a schedule-dependent manner? Context: Protein kinase inhibitors (PKI) have become prominent agents in cancer therapeutics. However, the specificity for target kinase inhibition can be poor and unwanted effects can emerge in combination regimens. The PKI emodin, for instance, can produce mixed results when combined with cisplatin, and we have sought a biochemical pharmacologic explanation for the negative cytotoxic effects. Human ovarian A2780 tumor cells were exposed to the PKI emodin or dichloro-ribofuranosylbenzimidazole (DRB) with cisplatin using several schedules, and cytotoxicity determined by a growth inhibition assay. Intracellular platinum levels and DNA adducts were estimated by flameless atomic absorption spectrophotometry. When A2780 cells were exposed first to emodin or DRB and then to cisplatin alone, the cytotoxic effects of cisplatin were significantly enhanced, whereas simultaneous exposure did not enhance the cytotoxicity, but instead inhibited it in the case of DRB. The increase in activity of cisplatin in the sequenced schedule was not due to increases in intracellular levels of cisplatin or DNA adducts, whereas the cytotoxic inhibition was related to a significant fall in both intracellular platinum levels and DNA adducts, which were ascribed to inhibition in cisplatin uptake. Knockdown of hCtr1 (the human copper transporter 1) by siRNA abrogated this inhibition in cisplatin uptake.
assistant
The results demonstrate that co-exposure of tumor cells to emodin or DRB with cisplatin inhibits platinum drug uptake by impacting the hCtr1 transporter and, thereby, reduce the cytotoxicity of cisplatin. Based on our findings, scheduling of the PKI and the cytotoxic agent should be a major consideration in the clinical design of combination regimens. Final Decision: yes