학술논문
Valproic acid reprograms the metabolic aberration of cisplatin treatment via ALDH modulation in triple-negative breast cancer cells.
Document Type
Academic Journal
Author
Granit Mizrahi A; Oncology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.; School of Pharmacy, Institute for Drug Research, The Hebrew University, Jerusalem, Israel.; Gugenheim A; Oncology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.; Hamad H; Oncology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.; Hamed R; School of Pharmacy, Institute for Drug Research, The Hebrew University, Jerusalem, Israel.; Tetro N; School of Pharmacy, Institute for Drug Research, The Hebrew University, Jerusalem, Israel.; Maimon O; Oncology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.; Khutsurauli S; Oncology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.; Nechushtan H; Oncology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.; Nisman B; Oncology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.; Duran D; Faculty of Medicine, Hebrew University, Jerusalem, Israel.; Hadassah Organoid Center, The Hadassah Medical Organization, Jerusalem, Israel.; Samman W; Faculty of Medicine, Hebrew University, Jerusalem, Israel.; Hadassah Organoid Center, The Hadassah Medical Organization, Jerusalem, Israel.; Birimberg-Schwartz L; Faculty of Medicine, Hebrew University, Jerusalem, Israel.; Hadassah Organoid Center, The Hadassah Medical Organization, Jerusalem, Israel.; Department of Pediatric Gastroenterology, The Hadassah Medical Organization, Jerusalem, Israel.; Grunewald M; Faculty of Medicine, Hebrew University, Jerusalem, Israel.; Hadassah Organoid Center, The Hadassah Medical Organization, Jerusalem, Israel.; Eyal S; School of Pharmacy, Institute for Drug Research, The Hebrew University, Jerusalem, Israel.; Peretz T; Oncology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.; Faculty of Medicine, Hebrew University, Jerusalem, Israel.
Source
Publisher: Frontiers Media S.A Country of Publication: Switzerland NLM ID: 101630250 Publication Model: eCollection Cited Medium: Print ISSN: 2296-634X (Print) Linking ISSN: 2296634X NLM ISO Abbreviation: Front Cell Dev Biol Subsets: PubMed not MEDLINE
Subject
Language
English
ISSN
2296-634X
Abstract
We recently demonstrated that the histone deacetylase inhibitor valproic acid (VPA) reprograms the cisplatin-induced metabolome of triple-negative breast cancer (TNBC) cells, including a shift in hexose levels. Accordingly, here, we tested the hypothesis that VPA alters glucose metabolism in correlation with cisplatin sensitivity. Two TNBC cell lines, MDA-MB-231 (a cisplatin-resistant line) and MDA-MB-436 (a cisplatin-sensitive line), were analyzed. The glycolysis and oxidative metabolism were measured using the Glycolysis Stress Test kit. The expression of aldehyde dehydrogenases (ALDHs), enzymes linked to drug resistance, was investigated by Western blot and real-time PCR analyses. We additionally studied the influence of ALDH inhibition by disulfiram on the viability of MDA-MB-231 cells and on a TNBC patient-derived organoid system. Cisplatin treatment reduced the extracellular acidification rate in MDA-MB-436 cells but not MDA-MB-231 cells, whereas VPA addition increased the extracellular acidification rate in both cell lines. VPA further reduced the oxygen consumption rate of cisplatin-treated MDA-MB-436 cells, which correlated with cell cycle alterations. However, in MDA-MB-231 cells, the cell cycle distribution did not change between cisplatin/VPA-cisplatin treatments. In both cell lines, VPA increased the expression of ALDH isoform and ALDH1A1 expression. However, only in MDA-MB-231 cells, VPA synergized with cisplatin to augment this effect. Disulfiram sensitized the cells to the cytotoxic effects of the VPA-cisplatin combination. Furthermore, the disulfiram-VPA-chemotherapy combination was most effective in TNBC organoids. Our results show that ALDH overexpression may act as one mechanism of cellular resistance to VPA in TNBC and that its inhibition may enhance the therapeutic efficacy of VPA-chemotherapeutic drug combinations.
Competing Interests: SE has served as a consultant for Biopass and TrueMed, Israel. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Granit Mizrahi, Gugenheim, Hamad, Hamed, Tetro, Maimon, Khutsurauli, Nechushtan, Nisman, Duran, Samman, Birimberg-Schwartz, Grunewald, Eyal and Peretz.)
Competing Interests: SE has served as a consultant for Biopass and TrueMed, Israel. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Granit Mizrahi, Gugenheim, Hamad, Hamed, Tetro, Maimon, Khutsurauli, Nechushtan, Nisman, Duran, Samman, Birimberg-Schwartz, Grunewald, Eyal and Peretz.)