Nitro-Substituted Benzylic Organochalcogenides as Anticancer Agents: Unravelling the Multifaceted Pathways to Combat Triple-Negative Breast Cancer

Organochalcogens exhibit promising chemotherapeutic potential
against
several cancer types. However, their ability to simultaneously target
interconnected oncogenic signaling networks remains mostly unexplored.
Herein, we report 4-nitro-substituted benzylic diselenide 7, which exhibits concerted inhibition of Akt/mTOR and ERK pathways
with the suppression of NF-κB-mediated inflammation and invasiveness
against the highly aggressive triple-negative breast cancer MDA-MB-231
cells. Detailed mechanistic investigations illustrated that diselenide 7 induces ROS, leading to DNA damage, mitochondrial dysfunction,
and consequent suppression of the Akt/mTOR-ERK1/2 signaling axis,
leading to cellular death. Furthermore, the potency of 7 was validated in Swiss albino mice bearing breast adenocarcinoma,
with a markedly reduced tumor volume, downregulation of VEGF/MMP-9
expressions indicating impaired angiogenesis/metastasis, and the expansion
of life span. This work exemplifies distinctive mechanistic insights
into the multitargeting agent diselenide 7, highlighting
its potential as an anticancer therapeutic and paving the way for
the development of small-molecule organoselenium compounds for the
effective treatment of cancer.