Diindolylmethane Promotes Metabolic Crisis and Enhances the Efficacy of Centchroman in Breast Cancer: A 1 H NMR-Based Approach.

Diindolylmethane (DIM) is a key metabolite of indole-3-
carbinol found in cruciferous vegetables such as broccoli, cauliflower, and
cabbage. DIM has been known for its anti-cancerous activity through various
mechanisms. Most cancer cells, including triple-negative breast cancer
(TNBC), adapt distinct metabolic reprogramming for rapid growth and
proliferation. Hence, targeting metabolic dysregulation may provide a
favorable therapeutic condition for the treatment of TNBC. Earlier, we
found that DIM increases the intracellular accumulation of Centchroman
(CC), a potential anticancer agent, thereby enhancing the therapeutic
potential of CC against breast cancer. However, the role of DIM in regulating
TNBC cellular metabolism remains unknown. In the current study, we
investigated the potential therapeutic interventions of DIM in TNBC and its
metabolic reprogramming in enhancing the efficacy of CC. We found that
DIM induced metabolic catastrophe in TNBC cells by regulating aerobic glycolysis and intermediate metabolism. Further, the DIM
and CC combination significantly inhibited the TNBC tumor growth in the 4T1-syngeneic model. The inhibition of tumor growth
was associated with the downregulation of key aerobic glycolysis mediators such as PKM2, GLUT1, and hypoxia-inducible factor 1α
(HIF-1α). This is a first-of-a-kind investigation linking DIM with aerobic glycolysis regulation and enhancing the treatment efficacy
of CC against TNBC. Therefore, these findings suggest that DIM-based nutraceuticals and functional foods can be developed as
adjuvant therapy for treating metabolically dysregulated TNBC