Combination Effect of Bowman-Birk Inhibitor and α-Tocopheryl Succinate on Prostate Cancer Stem-Like Cells

Abstract

The reoccurrence of androgen-dependent prostate cancer after anti-androgen therapy mainly depends on prostate cancer stem-like cells. To reduce the risk, it is important to delete the cancer stem-like cells. Furthermore, to induce differentiation of cancer stem-like cells is critical to abrogate stemness of the cells. Therefore, we tried to investigate a possibility on the establishment of a new effective therapy to eradicate the cancer stemlike cells via the induction of differentiation in this study. Prostate cancer stem-like cells from an androgen-dependent prostate cancer cell line (LNCaP cell) had severe resistance against an anti-androgen therapeutic agent. We selected Bowman-Birk inhibitor (BBI) from soybeans reported as a chemopreventive agent in prostate cancer to differentiate the caner stem-like cells and a-tocopheryl succinate (TOS) known as a mitocan to induce effectively cytotoxic effect against the cancer stem-like cells. In fact, only TOS treatment had cytotoxic effect against the cancer stem-like cells, but the addition of BBI treatment to the cells treated with TOS reinforced TOS-mediated cytotoxicity in the cancer stem-like cells. This reinforcement coincided with the combination-enhanced apoptosis in the stem-like cells. Also, we confirmed caspase9-caspase3 cascade mainly contributed to the enhancement of the cytotoxicity in the stem-like cells caused by the combination, indicating that the reinforcement of BBI on TOS-mediated apoptosis via mitochondria related to the enhancing cytotoxic effect of the combination on the prostate cancer stem-like cells. Overall, it seems that the combination is an effective new approach to reduce the reoccurrence of prostate cancer targeting prostate cancer stem cells.

The Effect of Bowman-Birk Inhibitor from Soybeans on the Sensitivity of Prostate Cancer Stem-like Cells to Anti-androgen Agent

“…2B, there was a significant increase in sphere formation capability in LNCaP stem-like cells compared with LNCaP parental cells, and BBI treatment suppressed the sphere formation capacity in LNCaP stem-like cells with a statistical significance. Similarly with the above observation, our previous report indicated that LNCaP stem-like cells, but not LNCaP parental cells, could exhibit resistance to flutamide (Kaneko et al, 2019). In this study, we demonstrated that concomitant treatment with a fixed dose of BBI almost abolished this resistance with a flutamide induced dose-dependent reduction in cell viability in LNCaP stem-like cells (Fig.…”

“…We then investigated whether BBI reduced stemness and resistance to ADT in LNCaP stem-like cells. The treatment dose of BBI was fixed at 200 μg/mL, as the cell growth control effect of BBI on LNCaP reached a plateau at this dose in a prior study (Kaneko et al, 2019). The results obtained showed that the BBI treatment significantly suppressed the levels of three cancer stem cell markers (CD24, CD44, and CD133) and slightly reduced the levels of the two other markers (SOX2 and Oct3/4) (Fig.…”

Bowman-Birk Inhibitors: Insights into Family of Multifunctional Proteins and Peptides with Potential Therapeutical Applications

“…stem-like cells [146] Combination of BBI and α-tocopheryl succinate results in cell growth inhibition and induction of apoptosis. BBI at the concentration of 200 µg/mL.…”

“…Kaneko et al [146] demonstrated the capability of soybean BBI to reinforce cytotoxicity induced by α-tocopheryl succinate (TOS) mitocan. As compared with individual BBI and TOS treatments, the combined application of these both agents resulted in a significant decrease in cell viability of prostate cancer cells (LNCaP) and undifferentiated prostate stem-like cells, which are more resistant to chemotherapy.…”