Novel Sulforaphane Analog Disrupts Phosphatidylinositol-3-Kinase-Protein Kinase B Pathway and Inhibits Cancer Cell Progression via Reactive Oxygen Species-Mediated Caspase-Independent Apoptosis

Ananya Dutta; Satyajit Halder; Ishani Bhaumik; Utsab Debnath; Debashis Dhara; Anup Kumar Misra; Kuladip Jana

doi:10.1021/acsptsci.3c00229

Novel Sulforaphane Analog Disrupts Phosphatidylinositol-3-Kinase-Protein Kinase B Pathway and Inhibits Cancer Cell Progression via Reactive Oxygen Species-Mediated Caspase-Independent Apoptosis

ACS Pharmacol Transl Sci. 2023 Dec 12;7(1):195-211. doi: 10.1021/acsptsci.3c00229. eCollection 2024 Jan 12.

Authors

Ananya Dutta^{1

2}, Satyajit Halder^{1

2}, Ishani Bhaumik^{1

2}, Utsab Debnath³, Debashis Dhara^{1

2}, Anup Kumar Misra^{1

2}, Kuladip Jana^{1

2}

Affiliations

¹ Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700054, India.
² Bose Institute, EN 80, Sector V, Salt Lake City, Bidhannagar, Kolkata 700091, India.
³ School of Health Sciences & Technology, University of Petroleum and Energy Studies, Dehradun 248007, India.

PMID: 38230291
PMCID: PMC10789126 (available on 2024-12-12)
DOI: 10.1021/acsptsci.3c00229

Abstract

Sulforaphane, a naturally occurring isothiocyanate, has gained attention due to its tremendous anticancer potential. Thus, an array of sulforaphane analogs were synthesized and evaluated for their cytotoxic potentials on a wide range of malignant cell lines. Among these derivatives, compound 4a displayed exceptional potency in inhibiting the proliferation of cancer cell lines and a negligible effect on normal cell lines through G2/M phase arrest. The lead compound induced reactive oxygen species (ROS)-mediated mitochondrial dysfunction, leading to apoptosis. Further mechanistic studies established the interaction of the compound 4a with the insulin-like growth factor-1 receptor (IGF-R1) and blocking of the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (PKB/Akt) pathway. This led to suppression of nuclear factor erythroid 2-related factor 2 (NRF-2) protein expression, thus increasing the free radicals in the tumor cells. Moreover, compound 4a induced ROS-mediated caspase-independent apoptosis. Finally, compound 4a reduced tumor progression in a 4T1 injected BALB/c syngeneic mice tumor model. In conclusion, this study summarizes the mechanism of compound 4a-mediated ROS-mediated caspase-independent apoptosis. According to the study's findings, compound 4a can be used as a powerful new anticancer agent to enhance cancer treatment.