Truncated Bid Regulates Cisplatin Response via Activation of Mitochondrial Apoptosis Pathway in Ovarian Cancer

Abstract

Refractoriness to conventional chemotherapy is a major challenge in the treatment of advanced ovarian cancer (OC). There is increasing evidence that mitochondrial priming correlates with cisplatin response in various cancers. Notably, Bim and Bid, two of the proapoptotic BH3-only proteins, are recognized as the most effective inducers of mitochondrial priming in OC. In this study, we constructed two tumor-specific oncolytic adenoviruses (Ads) coding for Bim (Ad-Bim) or truncated Bid (Ad-tBid), respectively, and performed gain-of-function assays in nine OC cell lines. Ad-tBid exhibited significant antitumor efficacy than the controls. On addition of Ad-tBid pretreatment, mito-primed cells displayed more sensitivity to cisplatin both in vitro and ex vivo. We also found that Ad-tBid induced mitochondrial apoptosis in a Bakdependent manner. Furthermore, a combined cisplatin plus Ad-tBid therapy markedly inhibited tumor growth in a subcutaneous xenotransplanted tumor model. In mice bearing peritoneal disseminated OC, intraperitoneal administration of Ad-tBid potentiated the antitumor effect of cisplatin. Our findings suggest that Ad-tBid enhances cisplatin response in OC cells, establishing the potential treatment of advanced OC via a combination of cisplatin and Ad-tBid.

Bcl‑2 family: Novel insight into individualized therapy for ovarian cancer (Review)

“…BId is considered to be the most effective initiator among BH3-only proteins. When constructed into tumor-specific oncolytic adenoviruses, the overexpression of BId exhibited great antitumor activation and enhanced the chemosensitivity to cisplatin in 9 ovarian cancer cell lines, consistent with the effect in a subcutaneous tumor xenograft model (68).…”

Protective Effect of Penetratin Analogue‐Tagged SOD1 on Cisplatin‐Induced Nephrotoxicity through Inhibiting Oxidative Stress and JNK/p38 MAPK Signaling Pathway

“…Since cell apoptosis is involved in CP-induced mitochondrial dysfunction, which is accompanied by the loss of MMP [ 26 – 28 ], we next explored whether PSF-SOD1 could restore CP-induced MMP decrease. Control cells stained with JC-1 exhibited strong red fluorescence.…”

Gene Therapy for Malignant and Benign Gynaecological Disorders: A Systematic Review of an Emerging Success Story

“…Specifically, the in vitro and in vivo application of Ad-p53 resulted in the activation of apoptosis and taxolsensitisation in ovarian cancer cells [38], while Gendicine, a gene therapy product approved for clinical use by the Chinese FDA in 2003, is now demonstrating very promising results, leading to a 90% patient response rate and 100% peritoneal effusion resolution [37]. In a recent study, Dai et al [36] constructed two tumour-specific oncolytic adenoviruses coding for Bim (Ad-Bim) or truncated Bid (Ad-tBid) and performed gain-of-function assays in nine ovarian cancer cell lines. The authors observed increased cisplatin sensitisation and apoptosis following treatment with Ad-tBid in vitro and ex vivo, while following Ad-tBid intraperitoneal administration in mice with peritoneal disseminated ovarian cancer, they observed enhanced cisplatin-mediated anti-tumour effects [36].…”

“…In a recent study, Dai et al [36] constructed two tumour-specific oncolytic adenoviruses coding for Bim (Ad-Bim) or truncated Bid (Ad-tBid) and performed gain-of-function assays in nine ovarian cancer cell lines. The authors observed increased cisplatin sensitisation and apoptosis following treatment with Ad-tBid in vitro and ex vivo, while following Ad-tBid intraperitoneal administration in mice with peritoneal disseminated ovarian cancer, they observed enhanced cisplatin-mediated anti-tumour effects [36]. Lastly, in regard to the immunopotentiation approach, HER2/neu, a protein shown to be overexpressed in ovarian cancer [79], was delivered to dendritic cells (DCs) by an AAV and primed these cells to express a self-tumour antigen.…”