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.
Background: Familial cases of adult acute myeloid leukemia (AML) with germline-mutated CCAAT/enhancer-binding protein-α (CEBPA) gene are a rare entity classified in World Health Organization (WHO) classification 2016. Most families reported in the literature show an autosomal dominant inheritance pattern consistent with a single-gene mutation. Methods: Here we studied a Syrian family with four individuals suffering from AML for CEBPA gene mutations by Sanger sequencing. Results: The father, his three affected, and one yet unaffected child had the same mutation in the N-terminal region of CEBPA (c.198dupC), resulting in termination at Tyr67Leufs*41. All affected family members had a good primary response to chemotherapy and achieved complete remission. Conclusion: Overall, another AML family with CEBPA gene mutation is added to the literature, presenting with yet unreported FAB subtype M5 and absence of CD7 expression in some family members. K E Y W O R D S acute myeloid leukemia (AML), CEBPA gene, familial, germline, prognosis This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
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