Novel pharmacological effects of poly (ADP-ribose) polymerase inhibitor rucaparib on the lactate dehydrogenase pathway

• Published in: Biochemical and biophysical research communications Vol. 510; no. 4; pp. 501 - 507
• Main Authors: Nonomiya, Yuma, Noguchi, Kohji, Katayama, Kazuhiro, Sugimoto, Yoshikazu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.03.2019
• Subjects: Cell Line, Tumor; Female; Humans; Indoles - pharmacology; L-Lactate Dehydrogenase - metabolism; Lactic Acid - metabolism; LDHA; Olaparib; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; PARP1; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Pyruvic Acid - metabolism; Rucaparib; Signal Transduction - drug effects; LDHA; Olaparib; PARP1; Rucaparib; Ovarian cancer
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2019.01.133

Poly (ADP-ribose) polymerases (PARPs) are involved in various cellular events, including DNA repair. PARP inhibitors including olaparib and rucaparib, have been specially developed against breast and ovarian cancers deficient in DNA repair systems. In this study, we found that PARP1-defective olaparib-resistant A2780 cells (ola-R cells) cells were still sensitive to two PARP inhibitors, rucaparib and veliparib. Metabolomic analysis revealed that rucaparib suppressed the lactate dehydrogenase (LDH)-mediated conversion of pyruvic acid to lactic acid in A2780 cells, although olaparib did not. The inhibition of LDH by siRNA-mediated knockdown or by LDH inhibitors suppressed the growth of ovarian cancer cells. Our results suggested that the suppression of the LDH-associated pathway contributed to the pharmacological effects of rucaparib. •Several PARP inhibitors have been developed for clinical use in cancer chemotherapy.•PARP1-deficient A2780 cells are resistant to a PARP inhibitor olaparib, but not to another PARP inhibitor rucaparib.•Rucaparib suppresses lactate dehydrogenase (LDH)-mediated pyruvate to lactate metabolism in ovarian cancer cells.•Suppression of LDH-pathway shows antiproliferative effect on ovarian cancer cells.