9h-purine-9-propanamine--6-amino-8-((6-iodo-1-3-benzodioxol-5-yl)thio)-n-(1-methylethyl)- and Triple-Negative-Breast-Neoplasms

Prodigiosin, a secondary metabolite red pigment produced by Serratia marcescens, has an interesting apoptotic efficacy against cancer cell lines with low or no toxicity on normal cells. HSP90α is known as a crucial and multimodal target in the treatment of TNBC. Our research attempts to assess the therapeutic potential of prodigiosin/PU-H71 combination on MDA-MB-231 cell line. The transcription and protein expression levels of different signalling pathways were assessed. Treatment of TNBC cells with both drugs resulted in a decrease of the number of adherent cells with apoptotic effects. Prodigiosin/PU-H71 combination increased the levels of caspases 3,8 and 9 and decreased the levels of mTOR expression. Additionally, there was a remarkable decrease of HSP90α transcription and expression levels upon treatment with combined therapy. Also, EGFR and VEGF expression levels decreased. This is the first study to show that prodigiosin/PU-H71 combination had potent cytotoxicity on MDA-MB-231 cells; proving to play a paramount role in interfering with key signalling pathways in TNBC. Interestingly, prodigiosin might be a potential anticancer agent to increase the sensitivity of TNBC cells to apoptosis. This study provides a new basis for upcoming studies to overcome drug resistance in TNBC cells.

Topics: Antineoplastic Agents; Apoptosis; Benzodioxoles; Caspases; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Evaluation, Preclinical; ErbB Receptors; Female; HSP90 Heat-Shock Proteins; Humans; Prodigiosin; Purines; Signal Transduction; TOR Serine-Threonine Kinases; Triple Negative Breast Neoplasms; Vascular Endothelial Growth Factor A

Due to the lack of markers (ER, PR, and HER-2/Neu) for the molecular-targeted therapies triple-negative breast cancer (TNBC) is more challenging than other subtypes of breast cancer. Moreover, the conventional chemotherapeutic agents are still the mainstay of most therapeutic protocols and eventually turn into a refractory drug-resistance , hence, more efficient therapeutic regimens are urgently required. The present study aimed to elucidate the effects of PU-H71 combined with DHEA on triple-negative breast cancer cell line MDA-MB-231 and to assess the synergy using the Chou-Talalay method. The combined therapy controlled the expression of an array of antioxidants and metabolizing enzymes, leading to the induction of oxidative stress which in turn induced apoptotic cell death. Our results indicated that the combined treatment with PU-H71 and DHEA exerts a synergistic anti-tumor effect on MDA-MB-231 triple-negative breast cancer cell line.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzodioxoles; Caspases; CDC2 Protein Kinase; Cell Line, Tumor; Dehydroepiandrosterone; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Glucosephosphate Dehydrogenase; HSP90 Heat-Shock Proteins; Humans; Ki-67 Antigen; Models, Biological; NF-E2-Related Factor 2; Purines; Triple Negative Breast Neoplasms