Sunitinib reduces tumor hypoxia and angiogenesis, and radiosensitizes prostate cancer stem‐like cells

Abstract

Our results support the use of Sunitinib in prostate cancer and shows that both hypoxia and cancer stem cells are involved in the effect elicited by this drug. Combination of Sunitinib with radiotherapy warrants further consideration to reduce prostate cancer burden.

Antitumor effect of sunitinib in human prostate cancer cells functions via autophagy

“…Our findings are in accordance with the results of two previous studies, concerning anti-tumor and radiosensitivity of sunitinib on PC-3 and DU145 cells in vitro (31) and the preventative effects in the course from non-castration to castration of LNCaP xenograft prostate (19). In addition, cell cycle analysis in the present study revealed that, following 10 µM of sunitinib treatment for 24 h, the number of PC-3 and LNCaP cells in S and G2/M phases was decreased, whereas the number of cells in G1 phase was increased, when compared with the controls.…”

“…Furthermore, the highly selective MEK1/2 inhibitor, U0126, markedly reversed the induction of autophagy by sunitinib when compared with the sunitinib and U0126 combination group and the sunitinib group, which suggested that ERK signaling may have a role in sunitinib-induced autophagy. However, Diaz et al (31) reported that sunitinib promoted a decrease in the expression level of p-ERK in PC-3 cells after treatment. Considering that the maximum concentration of sunitinib used by Diaz et al (31) employed in that study was 5 µM, which is much lower than that of our study, both results may be reasonable and further research is required.…”

“…However, Diaz et al (31) reported that sunitinib promoted a decrease in the expression level of p-ERK in PC-3 cells after treatment. Considering that the maximum concentration of sunitinib used by Diaz et al (31) employed in that study was 5 µM, which is much lower than that of our study, both results may be reasonable and further research is required. It has been established that mTORC1 may suppress autophagy by promoting phosphorylation and inactivation of proteins involved in autophagosome formation (47,48).…”

Tyrosine kinase inhibitors target cancer stem cells in renal cell cancer

“…In this study, CD24 + CD44 + ESA + triplepositive pancreatic CSCs were shown to be responsive to this TKI in combination with liposome-coated doxorubicin (12). In prostate cancer, in a PC3 cell-based model, sunitinib was shown to reduce the number of ALDH + cancer stem-like cells, and to sensitize these cells to the radiation-mediated loss of clonogenicity (13). In xenograft RCC models, sunitinib has been shown to generate resistance to its own therapeutic mechanism due to the induction of hypoxia in perinecrotic areas.…”

Molecularly targeted radiosensitization chances towards gene aberration-due organ confined/regionally advanced prostate cancer radioresistance

“…So far, the field of radioresistance conditions is often restricted to tumor microenvironmental hypoxia as low levels of reactive oxygen species (ROS) notoriously driving the cancer cells, by the development of the antiapoptotic hypoxia-inducible factor 1 (HIF 1), to radiation refractoriness onset. However, such radiobiological feature is so common of solid tumors -as it carefully detectable today by realtime mapping pO 2 tissue fluctuations with resort to electron paramagnetic resonance and, in case of intraoperative radiotherapy, to phosphorescent ruthenium-nitroimidazole optical imaging -that it shouldn't be defined as a genomic individual condition involving really customized radiosensitizer approaches (8,9). …”