Recombinant human PDCD5 sensitizes chondrosarcomas to cisplatin chemotherapy in vitro and in vivo

Abstract

Clinical management of chondrosarcoma remains a challenging problem, largely due to the toxicity and resistance of this tumor to conventional chemotherapy. Programmed Cell Death 5 (PDCD5) is a protein that accelerates apoptosis in different cell types in response to various stimuli, and has been shown to be down-regulated in many cancer tissues. In this study, mRNA and protein levels of PDCD5 were found to be up-regulated in cisplatin-treated SW1353 chondrosarcoma cells compared with untreated cells. Recombinant human PDCD5 (rhPDCD5) was also shown to sensitize chondrosarcoma cells to cisplatin-based chemotherapy, with inhibition of cell growth and apoptosis detected both in vitro and in vivo. Increased expression of Bax and decreased expression of Bcl-2 were also observed, along with release of cytochrome c from mitochondria into the cytosol. Additionally, cleavage of caspase-9 and caspase-3, as well as the cleavage of poly (ADP-ribose) polymerase (PARP), were detected, suggesting that sensitization of chondrosarcoma cells involves the intrinsic mitochondrial apoptosis pathway. In vivo, the treatment of a xenograft model of chondrosarcoma with rhPDCD5 and cisplatin significantly inhibited tumor cell proliferation and induced apoptosis compared to treatment with cisplatin alone. Overall, these data provide a theoretical basis for the administration of rhPDCD5 and cisplatin for the treatment of patients with chondrosarcoma.

PDCD5 promotes cisplatin-induced apoptosis of glioma cells via activating mitochondrial apoptotic pathway

“…This conclusion is consistent with previous reports in chondrosarcoma 21 and colorectal cancer. 22 Taken together, previous research and our data indicate that PDCD5 promotes chemosensitivity of malignant tumors by activating mitochondrial pathway. Therefore, combination of PDCD5 with chemotherapeutic agents is expected to be a very effective strategy for the treatment of tumors.…”

“…The results are in accordance with previous reports which showed that PDCD5 sensitizes chondrosarcomas or colorectal cancer to cisplatin chemotherapy. 21,22 In addition, we found that PDCD5 also increased chemosensitivity to CBDCA and VCR. However, PDCD5 had no significance effect on sensitivity of glioma cells to VP16.…”

“…It has been reported that adenovirus carrying PDCD5 possesses a potent antitumor effect, 21,24 and exogenous human PDCD5 protein has also antitumor activities. 22,25 Thus, combination of PDCD5 protein or gene with chemotherapeutic drugs may be a new strategy for tumor treatment including glioma.…”

Construction and characterization of a PDCD5 recombinant lentivirus vector and its expression in tumor cells

“…A combination of both in vitro and in vivo experiments confirmed that tumor cells expressing PDCD5 or treated with recombinant PDCD5 protein were more sensitive to chemotherapeutic drugs and UV irradiation. For example, mice with tumors expressing PDCD5 and treated with chemotherapy or radiation showed increased apoptosis, decreased tumor growth, and prolonged survival (8)(9)(10)(11)(12). These results support a role for PDCD5 as a tumor suppressor that influences treatment and prognosis.…”

“…Instead, it seems to be a pro-apoptotic factor that cooperates with chemotherapy or UV irradiation to cause cell death (8)(9)(10)(11)(12). In several studies, increased PDCD5 expression is accompanied by its translocation from the cytoplasm to the nucleus, a process that occurs prior to cell death.…”