Bicarbonate Attenuates Irinotecan-Induced Cytotoxicity through Regulation of Both Extracellular and Intracellular pHs in Intestine Cell Line

Teruo Miyazaki, Tadashi Ikegami, Yoshiaki Nagai, Amy Nguyen, Yasushi Matsuzaki, Kunihiko Kobayashi, Susan Ceryak

Department of Biochemistry and Molecular Biology, The George Washington University, Washington DC, USA.
Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan.
Department of Pharmacology, The George Washington University, Washington DC, USA.
Department of Respiratory Medicine, Saitama International Medical Center, Saitama Medical University, Hidaka, Saitama, Japan.
Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan.

DOI: 10.4236/jct.2013.45106                

Abstract

The anti-cancer therapy of irinotecan (CPT-11) is often limited due to severe late-onset diarrhea. Because the higher toxic form of CPT-11/its active metabolite (SN-38) is produced at acidification, the usefulness of oral sodium bicarbonate treatment against the CPT-11/SN-38-induced intestinal injuries and diarrhea has been confirmed. However, the roles of bicarbonate have been suggested to affect not only intestinal pH environment but also intracellular pH and CPT-11/SN-38 dynamics. The present study proposed to clarify the hypothesis in CPT-11/SN-38-exposed colon cell line in various pH conditions adjusted by bicarbonate. HT29 cell pre-exposed to ~1.0 μM SN-38 lactone or carboxylate forms was incubated at different pH adjusted by either bicarbonate or HCl/NaOH. The degrees of SN-38-induced cell injury depended on the higher proportion of the toxic form (lactone) of SN-38 rather than mere pH condition of medium. Apoptosis and cell injury induced by SN-38 were significantly inhibited by bicarbonate in a dose-dependent manner. Intercellular pH acidification induced by SN-38 was significantly prevented by 30 mM bicarbonate. Cell cytotoxicity of SN-38 depended on not only extracellular but also intracellular pH that converts the SN-38 form, while the intracellular acidification was prevented by bicarbonate. The multiple regulations of bicarbonate on both exracellular and intracellular pH would be essential mechanism against intestinal cell injury by CPT-11/SN-38.

Keywords

Bicarbonate; SN-38; CPT-11; pHi; Anti-Cancer Drug; Intestine

Conflicts of Interest

The authors declare no conflicts of interest.

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