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Dorzolamide synergizes the antitumor activity of mitomycin C against Ehrlich’s carcinoma grown in mice: role of thioredoxin-interacting protein

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Abstract

The antitumor activity of carbonic anhydrase (CA) inhibitors is attributed to their ability to induce a state of intracellular acidification. In fact, acidic intracellular pH was demonstrated to upregulate several tumor suppressor proteins and increase the activity of many chemotherapies. The present study aimed to investigate the antitumor activity of the CA inhibitor, dorzolamide, in combination with mitomycin C and to study the effect of these drugs on tumoral thioredoxin-interacting protein (TXNIP) as well as tumor cell proliferation and apoptosis. Solid tumors were induced by subcutaneous inoculation of Ehrlich’s ascites carcinoma (EAC) cells in female mice. Mice were treated with dorzolamide (3, 10, or 30 mg/kg/day, i.p.) and/or mitomycin C (1 mg/kg, i.p.) weekly for 3 weeks. Treatment with mitomycin C increased TXNIP level in EAC solid tumors in mice. Likewise, treatment with dorzolamide upregulated TXNIP and p53 while downregulated bcl-2. Both drug therapies increased tumoral caspase 9, caspase 3, and PARP-1 cleavage in addition to decreasing the proliferative Ki-67-stained nuclear fraction. Indeed, a synergistic effect was detected between mitomycin C and dorzolamide. The current data demonstrated that the antitumor activity of mitomycin C and dorzolamide was, at least in part, mediated through stimulating tumoral expression of TXNIP and enhancing tumor apoptosis.

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Acknowledgments

The authors wish to acknowledge Dr. Abeer Kamal, Faculty of Dentistry, Cairo University and Mr. Moussa Abd-Alghani, Pathology Lab., National Cancer Institute for their help in immunostaining. The authors also wish to thank Dr. Mohamed Kamal, Pathology Department, Faculty of Medicine, Suez Canal University for his help in photography.

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The authors declare that they have no competing interests.

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Correspondence to Sawsan A. Zaitone.

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Ali, B.M., Zaitone, S.A., Shouman, S.A. et al. Dorzolamide synergizes the antitumor activity of mitomycin C against Ehrlich’s carcinoma grown in mice: role of thioredoxin-interacting protein. Naunyn-Schmiedeberg's Arch Pharmacol 388, 1271–1282 (2015). https://doi.org/10.1007/s00210-015-1163-9

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  • DOI: https://doi.org/10.1007/s00210-015-1163-9

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