Valproic acid reprograms the metabolic aberration of cisplatin treatment via ALDH modulation in triple-negative breast cancer cells

Avital Granit Mizrahi; Ahinoam Gugenheim; Haneen Hamad; Roa'a Hamed; Nino Tetro; Ofra Maimon; Salome Khutsurauli; Hovav Nechushtan; Benjamin Nisman; Deborah Duran; Widad Samman; Liron Birimberg-Schwartz; Myriam Grunewald; Sara Eyal; Tamar Peretz

doi:10.3389/fcell.2023.1217149

Valproic acid reprograms the metabolic aberration of cisplatin treatment via ALDH modulation in triple-negative breast cancer cells

Front Cell Dev Biol. 2023 Oct 26:11:1217149. doi: 10.3389/fcell.2023.1217149. eCollection 2023.

Authors

Avital Granit Mizrahi^{1

2}, Ahinoam Gugenheim¹, Haneen Hamad¹, Roa'a Hamed², Nino Tetro², Ofra Maimon¹, Salome Khutsurauli¹, Hovav Nechushtan¹, Benjamin Nisman¹, Deborah Duran^{3

4}, Widad Samman^{3

4}, Liron Birimberg-Schwartz^{3

4

5}, Myriam Grunewald^{3

4}, Sara Eyal^#², Tamar Peretz^#^{1

3}

Affiliations

¹ Oncology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
² School of Pharmacy, Institute for Drug Research, The Hebrew University, Jerusalem, Israel.
³ Faculty of Medicine, Hebrew University, Jerusalem, Israel.
⁴ Hadassah Organoid Center, The Hadassah Medical Organization, Jerusalem, Israel.
⁵ Department of Pediatric Gastroenterology, The Hadassah Medical Organization, Jerusalem, Israel.

^# Contributed equally.

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.

Keywords: ALDH; GLUT1; aldehyde dehydrogenase; cisplatin; disulfiram; glucose; metabolism; valproic acid.

Grants and funding

This study was kindly supported by the Israel Cancer Association, Grant #20211181 and the David R. Bloom Centre for Pharmacy. HN was kindly supported by a grant from the Sasson Naor Foundation.