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Enhanced antitumor activity by combining an adenovirus harboring ING4 with cisplatin for hepatocarcinoma cells
1Cell and Molecular Biology Institute, College of Medicine, Soochow University, Suzhou, China.
Abstract:
The inhibitor of growth (ING) family proteins have been defined as candidate tumor suppressors. ING4 as a novel member of the ING family has potential tumor-suppressive effects. In this study, we explored the combined effect of adenovirus-mediated ING4 (Ad-ING4) gene transfer plus chemotherapy drug cisplatin (CDDP) on SMMC-7721 human hepatocarcinoma cells in vitro and in vivo, and its underlying mechanism. We demonstrated that Ad-ING4 plus CDDP induced synergistic growth inhibition, enhanced apoptosis, and had an additive effect on upregulation of Fas, Bax, Bak, cleaved Bid, cleaved caspase-8, caspase-9, caspase-3 and cleaved PARP, and on downregulation of Bcl-2 and Bcl-X(L) in SMMC-7721 hepatocarcinoma cells. Moreover, Ad-ING4 plus CDDP synergistically suppressed in vivo SMMC-7721 hepatocarcinoma subcutaneous (s.c.) xenografted tumor growth and reduced tumor vessel CD34 expression and microvessel density (MVD) in athymic nude mice. Most importantly, Ad-ING4 plus CDDP did not have overlapping toxicities in HL-7702 normal human liver cells and normal liver tissues of mice. The in vitro and in vivo enhanced antitumor effect elicited by Ad-ING4 plus CDDP was closely associated with the cooperative regulation of extrinsic and intrinsic apoptotic pathways and synergistic inhibition of tumor angiogenesis. Thus, our results indicate that Ad-ING4 plus CDDP is a potential combined treatment strategy for hepatocarcinoma.
Insights
Combining adenovirus-mediated ING4 gene transfer with cisplatin chemotherapy shows synergistic antitumor effects against hepatocarcinoma. This novel strategy enhances apoptosis and inhibits tumor growth and angiogenesis with minimal toxicity to normal liver cells.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Inhibitor of growth (ING) family proteins are recognized as potential tumor suppressors.
- ING4, a novel ING family member, exhibits potential tumor-suppressive properties.
Purpose of the Study:
- To investigate the combined effects of adenovirus-mediated ING4 (Ad-ING4) gene transfer and cisplatin chemotherapy (CDDP) on human hepatocarcinoma cells.
- To elucidate the underlying mechanisms of the combined treatment's efficacy both in vitro and in vivo.
Main Methods:
- Utilized adenovirus-mediated gene transfer for ING4 delivery.
- Administered cisplatin chemotherapy (CDDP) to SMMC-7721 hepatocarcinoma cells and xenografts.
- Assessed synergistic growth inhibition, apoptosis induction, and molecular pathway modulation.
- Evaluated in vivo tumor growth, angiogenesis markers (CD34, MVD), and toxicity in normal liver cells and tissues.
Main Results:
- Ad-ING4 plus CDDP demonstrated synergistic growth inhibition and enhanced apoptosis in hepatocarcinoma cells.
- The combination therapy upregulated pro-apoptotic factors (Fas, Bax, Bak, cleaved Bid, caspases) and downregulated anti-apoptotic proteins (Bcl-2, Bcl-X(L)).
- In vivo studies showed synergistic suppression of tumor growth, reduced tumor angiogenesis, and no overlapping toxicity in normal liver cells.
Conclusions:
- The combination of Ad-ING4 and CDDP exhibits a potent synergistic antitumor effect against hepatocarcinoma.
- This strategy effectively targets both extrinsic and intrinsic apoptotic pathways and inhibits tumor angiogenesis.
- Ad-ING4 plus CDDP represents a promising combined treatment approach for hepatocarcinoma with a favorable safety profile.
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