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H. Izumi, T. Torigoe, H. Ishiguchi, H. Uramoto, Y. Yoshida, M. Tanabe, T. Ise, T. Murakami, T. Yoshida, M. Nomoto and K. Kohno, “Cellular pH Regulators: Potentially Promising Molecular Targets for Cancer Chemotherapy,” Cancer Treatment Reviews, Vol. 29, No. 6, 2003, pp. 541-549. doi:10.1016/S0305-7372(03)00106-3

has been cited by the following article:

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

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

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

  JOURNAL NAME: Journal of Cancer Therapy, Vol.4 No.5, June 28, 2013

  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.