Aldehyde dehydrogenase inhibitors promote DNA damage in ovarian cancer and synergize with ATM/ATR inhibitors

Abstract

Rationale : Aldehyde dehydrogenase (ALDH) enzymes are often upregulated in cancer cells and associated with therapeutic resistance. ALDH enzymes protect cells by metabolizing toxic aldehydes which can induce DNA double stand breaks (DSB). We recently identified a novel ALDH1A family inhibitor (ALDHi), 673A. We hypothesized that 673A, via inhibition of ALDH1A family members, could induce intracellular accumulation of genotoxic aldehydes to cause DSB and that ALDHi could synergize with inhibitors of the ATM and ATR, proteins which direct DSB repair. Methods : We used immunofluorescence to directly assess levels of the aldehyde 4-hydroxynonenal and comet assays to evaluate DSB. Western blot was used to evaluate activation of the DNA damage response pathways. Cell counts were performed in the presence of 673A and additional aldehydes or aldehyde scavengers. ALDH inhibition results were confirmed using ALDH1A3 CRISPR knockout. Synergy between 673A and ATM or ATR inhibitors was evaluated using the Chou-Talalay method and confirmed in vivo using cell line xenograft tumor studies. Results : The ALDHi 673A cellular accumulation of toxic aldehydes which induce DNA double strand breaks. This is exacerbated by addition of exogenous aldehydes such as vitamin-A (retinaldehyde) and ameliorated by aldehyde scavengers such as metformin and hydralazine. Importantly, ALDH1A3 knockout cells demonstrated increased sensitivity to ATM/ATR inhibitors. And, ALDHi synergized with inhibitors of ATM and ATR, master regulators of the DSB DNA damage response, both in vitro and in vivo. This synergy was evident in homologous recombination (HR) proficient cell lines. Conclusions : ALDHi can be used to induce DNA DSB in cancer cells and synergize with inhibitors the ATM/ATR pathway. Our data suggest a novel therapeutic approach to target HR proficient ovarian cancer cells.

Precision Medicine for BRCA/PALB2-Mutated Pancreatic Cancer and Emerging Strategies to Improve Therapeutic Responses to PARP Inhibition

“…Accordingly, the ALDH1A1 inhibitor NCT-501 synergized with Olaparib in cell culture and xenograft models of BRCA2 -mutated ovarian cancer [ 104 ]. Similar results were observed using combined ALDH and ATM/ATR inhibitors in HR-proficient ovarian cancer cells, substantiating ALDH1A1 and related enzymes as a potential target for therapy [ 105 ].…”

Emerging Roles of Aldehyde Dehydrogenase Isoforms in Anti-cancer Therapy Resistance

“…Furthermore, a novel ALDH1A family inhibitor named 673A has been reported to increase cell death in ovarian cancer promoting aldehyde-mediated DNA damage. The synergistic combination between 673A, that indirectly increases DNA damage, and ATM/ATR inhibitors, that impair DNA repair, promotes cell death, representing a potential new therapeutic strategy for ovarian cancer patients ( 95 ). Disulfiram represents a potent ALDH1A1 and ALDH2 inhibitor used for the treatment of alcoholism ( 96 ).…”

ALDH1: A potential therapeutic target for cancer stem cells in solid tumors

“…Dual inhibition of Src and MEK reduces OC growth and targets ALDH1 (171). Consistent with these, ALDH1 inhibition effectively blocks the proliferation and survival of OC spheroids (167), and aldehyde dehydrogenase inhibitors promote OC DNA damage (172). IL-6-Nab combined with HMA completely eradicated OCSCs, and this combination blocked IL-6/IL6-R/pSTAT3mediated ALDH1A1 expression, providing a strategy for tumor recurrence after chemotherapy (173).…”