Bicarbonate Attenuates Irinotecan-Induced Cytotoxicity through Regulation of Both Extracellular and Intracellular <i>pHs</i> in Intestine Cell Line — Oak Academic Publishing
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Bicarbonate Attenuates Irinotecan-Induced Cytotoxicity through Regulation of Both Extracellular and Intracellular <i>pHs</i> in Intestine Cell Line
Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
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Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
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Department of Respiratory Medicine, Saitama International Medical Center, Saitama Medical University, Hidaka, Saitama, Japan
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Department of Biochemistry and Molecular Biology, The George Washington University, Washington DC, USA
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Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
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Department of Respiratory Medicine, Saitama International Medical Center, Saitama Medical University, Hidaka, Saitama, Japan
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Department of Pharmacology, The George Washington University, Washington DC, USA
1 Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
2 Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
3 Department of Respiratory Medicine, Saitama International Medical Center, Saitama Medical University, Hidaka, Saitama, Japan
4 Department of Biochemistry and Molecular Biology, The George Washington University, Washington DC, USA
5 Department of Internal Medicine, Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan
6 Department of Respiratory Medicine, Saitama International Medical Center, Saitama Medical University, Hidaka, Saitama, Japan
7 Department of Pharmacology, The George Washington University, Washington DC, USA
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 bicarbon ate 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 intracellu lar pH would be essential mechanism against intestinal cell injury by CPT-11/SN-38.
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