Inhibition of human lung cancer growth following adenovirus-mediated mda-7 gene expression in vivo

Abstract

Overexpression of the melanoma di erentiation associated gene-7 (mda-7) in vitro results in suppression of lung cancer cell proliferation. However, the ability of MDA-7 to suppress lung cancer in vivo has not been previously demonstrated. In this study, we investigated the possibility of inducing overexpression of the mda-7 gene in human non-small cell lung carcinoma cells in vivo and its e ects on tumor growth. Adenovirus-mediated overexpression of MDA-7 in p53-wild-type A549 and p53-null H1299 subcutaneous tumors resulted in signi®cant tumor growth inhibition through induction of apoptosis. In addition, decreased CD31/PECAM expression and upregulation of APO2/TRAIL were observed in tumors expressing MDA-7. In vivo studies correlated well with in vitro inhibition of lung tumor cell proliferation and endothelial cell di erentiation mediated by Ad-mda7. These data demonstrate that Ad-mda7 functions as a multi-modality anti-cancer agent, possessing both, pro-apoptotic and anti-angiogenic properties. We demonstrate for the ®rst time the potential therapeutic e ects of Ad-mda7 in human lung cancer.

Combinatorial synergy induced by adenoviral-mediated mda-7 and Herceptin in Her-2+ breast cancer cells

“…Differences in tumor size were analyzed for significance by the Student's t-test. Enhanced in vitro growth inhibitory and cytotoxic activity of Ad-mda7 and Herceptin in Her-2 þ breast cancer cells The antiproliferative effects of Ad-mda7 in various cancer cell types have been demonstrated in previous studies; [16][17][18][19][20][21][22][24][25][26][27][28][29][30][31][32][33][34]36 and the relevance of these findings to the clinical setting is supported by in vivo lung and breast xenograft models. 17,21 To corroborate that the Her-2 receptors expressed by the breast cancer cells are functional, we evaluated cell death in MDA-MB-453 and MCF-7 lines treated with increasing amounts of Herceptin (0-100 mg/ ml).…”

“…Ad-mda7 and Herceptin in Her-2 þ breast cancer D Bocangel et al Enhancement of apoptosis in Her-2 þ cells in vitro using a combination of Ad-mda7 and Herceptin We have previously shown that Ad-mda7 is able to rapidly induce apoptosis in various cancer cell lines, cell death being evident as early as 12 h post-transduction. 18,22,24 Here we evaluated the cytotoxic effects of Herceptin in breast cancer cells, using Annexin V staining, as a single agent and in combination with Ad-mda7. Treatment with Herceptin induced low-level apoptosis in Her-2 þ but not in Her-2À cells (Figure 2b).…”

“…[16][17][18] Studies using adenoviral-mediated mda-7 (Ad-mda7) have demonstrated that adenoviral-mediated overexpression of mda-7 has tumor-selective growth inhibitory, antiangiogenic and proapoptotic properties both, in vitro and in vivo. [18][19][20][21][22][23]38 It is now known that mda-7 activates various signaling pathways in a cell-type-specific manner, and that these pathways ultimately converge on mitochondrial destruction and induction of apoptosis. 21,22,[24][25][26][27][28][29][30] However, in spite of its clear tumor-suppressive effects, the mechanisms by which Ad-mda7 induces cytotoxicity have not been fully characterized.…”

The antitumor activity of TRAIL and IL-24 with replicating oncolytic adenovirus in colorectal cancer

“…46 It was reported that Ad-IL-24 could upregulate the expression of TRAIL in both H1299 and A549 tumor cells but not in normal cells. 8 But no further evidence was available. In this article, we reported that ZD55-IL-24 could obviously induce TRAIL expression as shown in Figure 2a, and both ZD55-IL-24 and its combination with ZD55-TRAIL could induce expression of the apoptotic death receptor DR4.…”

“…Previous studies have demonstrated that IL-24 can induce apoptosis at multiple levels by activating caspase cascade and upregulating P53, Bax, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and growth arrest and DNA damage protein family genes. [6][7][8] Additional mechanisms for IL-24-mediated cell killing have revealed its regulation of inducible nitric oxide synthase and mitogen-activated protein kinase in melanoma and JUN kinase, b-catenin, phosphatidylinositol 3 0 -kinase and double-stranded RNA-dependent protein kinase in lung and breast tumor cells. [9][10][11][12][13] Thus, IL-24 exerts its tumor-suppressive effects via different signaling pathways in different tumor types.…”