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

Yuma Nonomiya; Kohji Noguchi; Kazuhiro Katayama; Yoshikazu Sugimoto

doi:10.1016/j.bbrc.2019.01.133

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

Yuma Nonomiya, Kohji Noguchi, Kazuhiro Katayama, Yoshikazu Sugimoto

薬学科

研究成果: Article › 査読

11 被引用数 (Scopus)

抄録

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.

本文言語	English
ページ（範囲）	501-507
ページ数	7
ジャーナル	Biochemical and Biophysical Research Communications
巻	510
号	4
DOI	https://doi.org/10.1016/j.bbrc.2019.01.133
出版ステータス	Published - 2019 3月 19

ASJC Scopus subject areas

生物理学
生化学
分子生物学
細胞生物学

UN SDG

この成果は、次の持続可能な開発目標に貢献しています

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10.1016/j.bbrc.2019.01.133

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

abstract = "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.",

keywords = "LDHA, Olaparib, Ovarian cancer, PARP1, Rucaparib",

author = "Yuma Nonomiya and Kohji Noguchi and Kazuhiro Katayama and Yoshikazu Sugimoto",

note = "Funding Information: We thank Ayami Iwamoto and Yuri Mae for initial experiments of this study. This work was supported by JSPS KAKENHI Grant numbers 18K06632 to KN and 18K07302 to YS, and a Grant-in-Aid for JSPS Research Fellow 18J11600 to YN. We thank Editage ( www.ediateg.jp ) for English language editing. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

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doi = "10.1016/j.bbrc.2019.01.133",

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AU - Katayama, Kazuhiro

AU - Sugimoto, Yoshikazu

N1 - Funding Information: We thank Ayami Iwamoto and Yuri Mae for initial experiments of this study. This work was supported by JSPS KAKENHI Grant numbers 18K06632 to KN and 18K07302 to YS, and a Grant-in-Aid for JSPS Research Fellow 18J11600 to YN. We thank Editage ( www.ediateg.jp ) for English language editing. Publisher Copyright: © 2019 Elsevier Inc. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2019/3/19

Y1 - 2019/3/19

N2 - 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.

AB - 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.

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

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ASJC Scopus subject areas

UN SDG

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