A novel benzopyrane derivative targeting cancer cell metabolic and survival pathways

Dana M. Zaher, Wafaa S. Ramadan, Raafat El-Awady, Hany A. Omar, Fatema Hersi, Vunnam Srinivasulu, Ibrahim Y. Hachim, Farah I. Al-Marzooq, Cijo G. Vazhappilly, Salim Merali, Carmen Merali, Nelson C. Soares, Paul Schilf, Saleh M. Ibrahim, Taleb H. Al-Tel

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Article number2840
JournalCancers
Volume13
Issue number11
DOIs
Publication statusPublished - Jun 1 2021

Keywords

  • Apoptosis
  • Cell cycle
  • DNA damage
  • Glutathione reductase
  • Multitarget
  • Thioredoxin reductase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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