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Zaher DM , Ramadan WS , El-Awady R , Omar HA , Hersi F , Srinivasulu V , Hachim IY , Al-Marzooq FI , Vazhappilly CG , Merali S , Merali C , Soares NC , Schilf P , Ibrahim SM , Al-Tel TH
A Novel Benzopyrane Derivative Targeting Cancer Cell Metabolic and Survival Pathways
Cancers (Basel). 2021 Jun 7;13(11)
PMID: 34200264 PMCID: PMC8201054 URL: https://www.ncbi.nlm.nih.gov/pubmed/34200264
Abstract(1) Background: Today, the discovery of novel anticancer agents with multitarget effects and high safety margins represents a high challenge. Drug discovery efforts indicated that benzopyrane scaffolds possess a wide range of pharmacological activities. This spurs on building a skeletally diverse library of benzopyranes to identify an anticancer lead drug candidate. Here, we aim to characterize the anticancer effect of a novel benzopyrane derivative, aiming to develop a promising clinical anticancer candidate. (2) Methods: The anticancer effect of SIMR1281 against a panel of cancer cell lines was tested. In vitro assays were performed to determine the effect of SIMR1281 on GSHR, TrxR, mitochondrial metabolism, DNA damage, cell cycle progression, and the induction of apoptosis. Additionally, SIMR1281 was evaluated in vivo for its safety and in a xenograft mice model. (3) Results: SIMR1281 strongly inhibits GSHR while it moderately inhibits TrxR and modulates the mitochondrial metabolism. SIMR1281 inhibits the cell proliferation of various cancers. The antiproliferative activity of SIMR1281 was mediated through the induction of DNA damage, perturbations in the cell cycle, and the inactivation of Ras/ERK and PI3K/Akt pathways. Furthermore, SIMR1281 induced apoptosis and attenuated cell survival machinery. In addition, SIMR1281 reduced the tumor volume in a xenograft model while maintaining a high in vivo safety profile at a high dose. (4) Conclusions: Our findings demonstrate the anticancer multitarget effect of SIMR1281, including the dual inhibition of glutathione and thioredoxin reductases. These findings support the development of SIMR1281 in preclinical and clinical settings, as it represents a potential lead compound for the treatment of cancer.
Notes2072-6694 Zaher, Dana M Orcid: 0000-0001-5814-0784 Ramadan, Wafaa S El-Awady, Raafat Omar, Hany A Orcid: 0000-0002-4670-8149 Hersi, Fatema Orcid: 0000-0002-7122-4779 Srinivasulu, Vunnam Hachim, Ibrahim Y Orcid: 0000-0001-6438-9455 Al-Marzooq, Farah I Orcid: 0000-0001-5711-6264 Vazhappilly, Cijo G Orcid: 0000-0002-2742-6277 Merali, Salim Merali, Carmen Soares, Nelson C Orcid: 0000-0003-2331-8532 Schilf, Paul Ibrahim, Saleh M Al-Tel, Taleb H Orcid: 0000-0003-4914-9677 120403/Terry Fox Foundation/ 1801110125-P/University of Sharjah/ Journal Article Cancers (Basel). 2021 Jun 7;13(11):2840. doi: 10.3390/cancers13112840.