Targeting NQO1 Overexpression: The Selective Anti-Tumor Efficacy of SBSC-S3001 in Cancer Therapy

NAD(P)H-quinone oxidoreductase 1 (NQO1) is an enzyme that is overexpressed in a variety of cancers and is linked to resistance against oxidative stress and poor clinical outcomes. Its role in stabilizing the HIF-1α protein suggests that NQO1 could be a target for cancer therapy. A new synthetic NQO1 substrate, SBSC-S3001, has been found to selectively impact cancer cells with high NQO1 expression.

In vitro tests using the sulforhodamine B assay showed that SBSC-S3001 was cytotoxic to cancer cells with elevated NQO1 levels, and this effect was enhanced in both normoxic and hypoxic conditions. The compound influenced energy metabolism, mitochondrial function, and cancer cell proliferation. It was also more effective than beta-lapachone and its analogues in inducing cytotoxicity in NQO1-overexpressing cells.

Further analysis revealed that SBSC-S3001 treatment led to a decrease in glycolytic pathway enzymes (LDHa and GAPDH) and HIF-1α, while increasing mitochondrial oxidative phosphorylation (OXPHOS). In vivo studies using MC38 syngeneic and DLD-1 orthotopic mouse models demonstrated that SBSC-S3001 could inhibit tumor growth as a monotherapy.

The study concludes that SBSC-S3001, by targeting NQO1, reduces levels of HIF-1α and glycolytic enzymes, thereby suppressing tumor growth in cells that overexpress NQO1. This suggests that SBSC-S3001 could be a potential metabolic anti-cancer agent, warranting further investigation for use in cancers with high NQO1 levels.

The research was conducted ethically, with approval from Samyang Biopharmaceuticals Institution’s Ethics Board. This work contributes to the understanding of NQO1's role in cancer and the development of targeted therapies.