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

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DOI: 10.4236/jct.2013.45106    2,727 Downloads   4,089 Views   Citations

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.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

T. Miyazaki, T. Ikegami, Y. Nagai, A. Nguyen, Y. Matsuzaki, K. Kobayashi and S. Ceryak, "Bicarbonate Attenuates Irinotecan-Induced Cytotoxicity through Regulation of Both Extracellular and Intracellular pHs in Intestine Cell Line," Journal of Cancer Therapy, Vol. 4 No. 5, 2013, pp. 944-952. doi: 10.4236/jct.2013.45106.

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