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Therapeutic potential and molecular mechanism of a novel sulfonamide anticancer drug, indisulam (E7070) in combination with CPT-11 for cancer treatment

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Abstract

Purpose

Indisulam (N-(-3-chloro-7-indolyl)-1,4-benzenedisulfonamide; E7070) is an experimental anticancer agent. Microarray analysis indicates that indisulam downregulates several genes involved in drug resistance, and this finding led us to test the effect of combining indisulam with other anticancer drugs. We investigated the antitumor effect and mechanism of synergism when indisulam was administered in combination with CPT-11.

Methods

In vitro cytotoxic activity was examined using a cell counter kit, and the combination effect was determined by isobologram analysis. The level of topoisomerase IIα was measured by Western blotting. The in vivo antitumor effect was assessed in mice inoculated with human colorectal cancer SW620 cells.

Results

Isobologram analysis indicated that a 24-h exposure to indisulam and SN-38, an active metabolite of CPT-11, had a synergistic effect in HCT116 and SW620 cells and an additive effect in HCT15 and WiDr cells. Prolongation of exposure to 48 h resulted in a synergistic effect in HCT15 and WiDr cells. Treatment with SN-38 alone increased the amount of intracellular topoisomerase IIα in all cell lines tested. Co-treatment with indisulam suppressed the SN-38-induced upregulation of topoisomerase IIα after 24 h of exposure in HCT116 and SW620 cells and after 48 h of exposure in HCT15 and WiDr cells. This apparent association between a synergistic effect and suppression of SN-38-mediated upregulation of topoisomerase IIα suggests that indisulam enhances SN-38 cytotoxicity by suppressing topoisomerase IIα upregulation to compensate for topoisomerase I inhibition by SN-38. Synergy was also observed in xenografted tumors and was accompanied by complete suppression of topoisomerase IIα upregulation induced by CPT-11 treatment.

Conclusion

These observations prompted the clinical evaluation of indisulam and CPT-11 combination therapy.

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Acknowledgments

We thank Professor Fukamizu of the University of Tsukuba for giving advice on making the draft plan. SN-38 was kindly provided by Yakult Co. Ltd.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Oncology PCU, Eisai Co., Ltd., Ibaraki, Japan

    Yoichi Ozawa & Akira Yokoi

  2. BA CFU, Eisai Co., Ltd., Ibaraki, Japan

    Kazutomi Kusano

  3. Oncology PCU, Eisai Co., Ltd., Woodcliff Lake, NJ, USA

    Takashi Owa

  4. Eisai Co., Ltd., Tokyo, Japan

    Makoto Asada & Kentaro Yoshimatsu

Authors
  1. Yoichi Ozawa
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  2. Kazutomi Kusano
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  3. Takashi Owa
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  4. Akira Yokoi
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  5. Makoto Asada
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  6. Kentaro Yoshimatsu
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Corresponding author

Correspondence to Yoichi Ozawa.

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Ozawa, Y., Kusano, K., Owa, T. et al. Therapeutic potential and molecular mechanism of a novel sulfonamide anticancer drug, indisulam (E7070) in combination with CPT-11 for cancer treatment. Cancer Chemother Pharmacol 69, 1353–1362 (2012). https://doi.org/10.1007/s00280-012-1844-8

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  • DOI: https://doi.org/10.1007/s00280-012-1844-8

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