3-aminopyridine-2-carboxaldehyde-thiosemicarbazone and Prostatic-Neoplasms

The development of chemotherapy resistance in prostate cancer (PCa) patients poses a significant obstacle to disease progression. Ribonucleotide reductase is a crucial enzyme for cell division and tumor growth. Triapine, an inhibitor of ribonucleotide reductase, has shown strong anti-tumor activity in various types of cancers. However, the effect of triapine on docetaxel-resistant (DR) human PCa cells has not been explored previously.. This study aimed to examine the potential anti-proliferative effects of triapine in PC3-DR (docetaxel-resistant) cells.. Cell viability was determined by the MTT test, and apoptosis and cell cycle progression were analyzed by image-based cytometer. mRNA and protein expression were assessed by RT-qPCR and western blot, respectively.. Triapine administration significantly reduced PC3 and PC3-DR cells' survival, while the cytotoxic effect was higher in PC3-DR cells. Cell death resulting from inhibition of ribonucleotide reductase was mediated by endoplasmic reticulum stress, induction of apoptosis, and cell cycle arrest. The findings were supported by the upregulation of caspases, Bax, Bak, P21, P27, P53, TNF-α, FAS, and FASL, and downregulation of Bcl2, Bcl-XL, cyclin-dependent kinase 2 (CDK2), CDK4, cyclins, and heat shock proteins expression. According to the data, the reduction of ABC transporter proteins and NF-ĸB expression may play a role in triapine-mediated cytotoxicity in docetaxel-resistant cells.. Based on our findings, triapine emerges as a promising chemotherapeutic approach for combating docetaxel- resistant prostate cancer.

Topics: Apoptosis; Cell Line, Tumor; Docetaxel; Endoplasmic Reticulum Stress; Humans; Male; Prostatic Neoplasms; Ribonucleotide Reductases

The purpose of this study was to evaluate baseline RRM2 protein and gene expression in tumors of patients receiving 3-AP.. Tumor blocks from patients enrolled in phase I and II clinical studies using 3-AP, were evaluated for RRM2 gene and protein expression by quantitative real time polymerase chain reaction (Q-RTPCR) and automated quantitative analysis (AQUA).. Esophageal and gastric cancers overexpressed RRM2 protein when compared to prostate cancer (Z-score, 0.68 +/- 0.94 SD, vs 0.41 +/- 0.84 SD, respectively; p = 0.04). Esophageal and gastric cancers also overexpressed RRM2 mRNA when compared to prostate cancer (relative gene expression 2.56 +/- 1.49 SD, vs 0.29 +/- 0.20 SD, respectively; p = 0.02). Protein and gene expression were moderately associated (Spearman's rank correlation = 0.30; p = 0.12).. RRM2 gene and protein expression varies by tumor type.

Topics: Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Esophageal Neoplasms; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Male; Polymerase Chain Reaction; Prostatic Neoplasms; Protein Subunits; Pyridines; Ribonucleoside Diphosphate Reductase; RNA, Messenger; Stomach Neoplasms; Thiosemicarbazones

Because ribonucleotide reductase (RR) plays a role in DNA repair, it may serve as a molecular target for radiosensitization. Unlike previously investigated RR inhibitors, Triapine potently inhibits both RR holoenzymes. Therefore, the effects of Triapine on tumor cell radiosensitivity were investigated.. The effects of Triapine on the in vitro radiosensitivity of three human tumor cell lines and one normal cell line were evaluated using a clonogenic assay. Growth delay was used to evaluate the effects of Triapine on in vivo tumor radiosensitivity. The levels of the RR subunits were determined using immunoblot analysis and DNA damage and repair were evaluated using gammaH2AX foci.. Exposure of the tumor cell lines to Triapine before or immediately after irradiation resulted in an increase in radiosensitivity. In contrast, Triapine enhanced the radiosensitivity of the normal fibroblast cell line only when the exposure was before irradiation. There were no consistent differences between cell lines with respect to the expression of the RR subunits. Whereas Triapine had no effect on radiation-induced gammaH2AX foci at 1 hour, the number of gammaH2AX foci per cell was significantly greater in the Triapine-treated cells at 24 hours after irradiation, suggesting the presence of unrepaired DNA damage. Triapine administration to mice bearing tumor xenografts immediately after irradiation resulted in a greater than additive increase in radiation-induced tumor growth delay.. These results indicate that Triapine can enhance tumor cell radiosensitivity in vitro and in vivo and suggest that this effect involves an inhibition of DNA repair.

Topics: Cell Cycle; Cell Line, Tumor; Dose-Response Relationship, Radiation; Enzyme Inhibitors; Glioma; Humans; Male; Pancreatic Neoplasms; Prostatic Neoplasms; Pyridines; Radiation-Sensitizing Agents; Ribonucleotide Reductases; Thiosemicarbazones