Dietary Diindolylmethane Enhances the Therapeutic Effect of Centchroman in Breast Cancer by Inhibiting Neoangiogenesis

Abstract

Tumor angiogenesis is primarily regulated by vascular endothelial growth factor and its receptor (VEGF-VEGFR) communication, which is involved in cancer cell growth, progression, and metastasis. Diindolylmethane (DIM), a dietary bioactive from cruciferous vegetables, has been extensively studied in preclinical models for breast cancer prevention and treatment. Nevertheless, the possible role of DIM in the angiogenesis and metastasis regulations in triple-negative breast cancer (TNBC) remains elusive. Here, we investigated the potential anti-angiogenic and anti-metastatic role of DIM in combination with centchroman (CC). We observed that the oral administration of the DIM and CC combination suppressed primary tumor growth and tumor-associated vascularization in 4T1 tumors. Further, the DIM and CC combination exhibited a strong inhibitory effect on VEGF-induced angiogenesis in matrigel plugs. The mechanistic study demonstrated that DIM and CC could effectively downregulate VEGFA expression in tumor tissue and strongly interact with VEGFR2 to block its kinase activity. Interestingly, the DIM and CC combination also suppressed the lung metastasis of the highly metastatic 4T1 tumors through the downregulation of FAK/MMP9/2 signaling and reversal of epithelial-to-mesenchymal transition (EMT). Overall, these findings suggest that DIM-based nutraceuticals and functional foods can be developed as adjuvant therapy for treating TNBC.

Acknowledgments

DJ and PM acknowledge senior research fellowships from UGC, Government of India, and JN acknowledges senior research fellowship from DBT, Government of India.

Authors’ Contributions

DP performed the study, analyzed and wrote the manuscript, NJ and PM prepared the figures and wrote the manuscript, DP, NJ and PM edited and revised the manuscript, SMM Conceptualized, designed, interpreted and wrote the manuscript. All the authors have read and approved the final manuscript for publication.

Ethical Approval

The animal experiment was approved and conducted according to the institutional IAEC committee of CSIR-CFTRI, Mysore, India (Approval No. CFT/IAEC/105/2017)

Data Availability

All data generated or analyzed during this study are included in this article.

Disclosure Statement

The authors report there are no competing interests to declare.

Additional information

Funding

This study was supported by funding from CSIR-CFTRI (MLP-0250).