Dorzolamide synergizes the antitumor activity of mitomycin C against Ehrlich's carcinoma grown in mice: role of thioredoxin-interacting protein.
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.
Department of Pharmacology and Toxicology, Faculty of Pharmacy and Pharmaceutical Industries, Sinai University, Arish, Egypt.
Belal M
BM
Ali
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt. Sawsan_zaytoon@pharm.suez.edu.eg.
Sawsan A
SA
Zaitone
Department of Tumor Cell Biology, National Cancer Institute, Cairo University, Cairo, Egypt.
Samia A
SA
Shouman
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt.
Yasser M
YM
Moustafa
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy* / Q000473:pathology; D002352:Carrier Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D051379:Mice; D016685:Mitomycin / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D013876:Thiophenes / Q000627:therapeutic use*; D013879:Thioredoxins / Q000502:physiology*
D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D013449:Sulfonamides; D013876:Thiophenes; C445672:Txnip protein, mouse; D016685:Mitomycin; D013879:Thioredoxins; C062765:dorzolamide
Anticancer; Carbonic anhydrase; Dorzolamide; Ehrlich’s ascites carcinoma; Mitomycin C; TXNIP