Co-administration of sulforaphane and doxorubicin attenuates breast cancer growth by preventing the accumulation of myeloid-derived suppressor cells

Abstract

Sulforaphane (SFN) is a compound derived from cruciferous plants shown to be effective in cancer prevention and suppression. Myeloid-derived suppressor cells (MDSCs) are known to inhibit anti-tumor immunity; however, whether SFN regulates the anti-tumor activity of MDSCs in breast cancer is still unknown. In the current study, we found that SFN blocked prostaglandin E2 (PGE2) synthesis in parental and doxorubicin (DOX)-resistant breast cancer 4T1 cell lines by activating NF-E2-related factor 2 (Nrf2). Nrf2-mediated reduction of PGE2 was dependent on the enhanced expression of heme oxygenase 1 (HO-1) and glutamate-cysteine ligase (GCLC), and decreased COX-2 expression in breast cancer cells. Moreover, our study further revealed that reduced PGE2 secretion from SFN-treated 4T1 cells triggered MDSCs to switch to an immunogenic phenotype, enhancing the anti-tumor activities of CD8⁺ T cells. Co-administration of SFN and DOX was more efficacious for the treatment of breast cancer in a mouse model than either agent alone, as evidenced by the significant decrease in tumor volume, MDSC expansion, and increase in cytotoxic CD8⁺ T cells. Taken together, our data indicate that SFN reverses the immunosuppressive microenvironment and is a potent adjuvant chemotherapeutic candidate in breast cancer.

Keywords: Breast cancer; CD8(+) T cells; Doxorubicin; Myeloid-derived suppressor cells; Sulforaphane.