Bleomycin Induced Sensitivity to TRAIL/Apo-2L-Mediated Apoptosis in Human Seminomatous Testicular Cancer Cells is Correlated with Upregulation of Death Receptors

Abstract

The most common solid tumor is testicular cancer among young men. Bleomycin is an antitumor antibiotic used for the therapy of testicular cancer. TRAIL is a proapoptotic cytokine that qualified as an apoptosis inducer in cancer cells. Killing cancer cells selectively via apoptosis induction is an encouraging therapeutic strategy in clinical settings. Combination of TRAIL with chemotherapeutics has been reported to enhance TRAIL-mediated apoptosis of different kinds of cancer cell lines. The molecular ground for sensitization of tumour cells to TRAIL by chemotherapeutics might involve upregulation of TRAIL-R1 (TR/1, DR4) and/or TRAIL-R2 (TR/2, DR5) receptors or activation of proapoptotic proteins including caspases. The curative potential of TRAIL to eradicate cancer cells selectively in testicular cancer has not been studied before. In this study, we investigated apoptotic effects of bleomycin, TRAIL, and their combined application in NTera-2 and NCCIT testicular cancer cell lines. We measured caspase 3 levels as an apoptosis indicator, and TRAIL receptor expressions using flow cytometry. Both NTera-2 and NCCIT cells were fairly resistant to TRAIL's apoptotic effect. Incubation of bleomycin alone caused a significant increase in caspase 3 activity in NCCIT. Combined incubation with bleomycin and TRAIL lead to elevated caspase 3 activity in Ntera-2. Exposure to 72 h of bleomycin increased TR/1, TR/2, and TR/3 cell-surface expressions in NTera-2. Elevation in TR/1 cell-surface expression was evident only at 24 h of bleomycin application in NCCIT. It can be concluded that TRAIL death receptor expressions in particular are increased in testicular cancer cells via bleomycin treatment, and TRAIL-induced apoptosis is initiated.

Azithromycin enhances anticancer activity of TRAIL by inhibiting autophagy and up‐regulating the protein levels of DR4/5 in colon cancer cells in vitro and in vivo

“…TRAIL induces apoptosis via specific binding to DR4 and DR5. Moreover, several drugs (i.e., celecoxib, quinacrian, and bleomycin) sensitize certain types of cancer cells to apoptosis induced by TRAIL through increasing the protein levels of DR4 or DR5 [ 19 – 22 ]. We therefore suspect that the death receptor protein levels are implicated in the synergistic action between azithromycin and TRAIL.…”

Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs)

“…The apoptotic potential of TRAIL has shown to improve via combinatory treatment with etoposide, doxorubicin or paclitaxel mediated upregulation of both DR4 (TRAILI) and DR5 (TRAILII) expression in numerous breast cancer cells types in vitro, as well as in tumorigenic mice [169]. The anti-tumor antibiotic Bleomycin and the histone deacetylase inhibitor MS-275 have also upregulate DR4 and DR5 to sensitize cancer cells to TRAIL-induced apoptosis [170, 171]. Lastly, microtubulin targeting compound PBOX-15 (pyrrolo-1,5-benzoxazepine) treatment in myeloma in Jurkat ALL cells also resulted in an upregulation of DR5 to enhance TRAIL-induced apoptosis [172].…”

The pyrrolo-1,5-benzoxazepine, PBOX-15, enhances TRAIL-induced apoptosis by upregulation of DR5 and downregulation of core cell survival proteins in acute lymphoblastic leukaemia cells

“…TRAIL resistance mediated by agonist receptor expression levels can be overcome by combining TRAIL with agents that induce the expression of DR4 and DR5 on tumour cells. The chemotherapeutics etoposide, doxorubicin and paclitaxel ( 32 , 46 , 47 ), the antitumour antibiotic Bleomycin ( 48 ), and the histone deacetylase inhibitor MS-275 ( 49 ) have been shown amongst others to upregulate DR4 and DR5 and thus sensitise various cancer cells to TRAIL-induced apoptosis. Similarly, our group demonstrated that novel mictotubulin-targeting agent PBOX-15 synergistically enhanced TRAIL-induced apoptosis in myeloma cells via upregulation of DR5 ( 17 ).…”