Renal Cell Carcinoma (RCC) is among the most lethal and difficult tumors to treat, particularly when disease has spread beyond the kidney and into the surrounding fascia; even intensive combinations of radio- and chemotherapy are not curative and yield only a modest impact on patient survival. There is a major need for alternative therapeutic modalities. Expression of MDA-7/IL-24 in many different tumor cell types causes growth arrest and apoptosis whereas in non-transformed cells it alters neither cell growth nor cell survival. Previous studies have shown that MDA-7 administered either as a virus (Ad.mda-7), as a purified fusion protein (GST-MDA-7), or in conditioned media, suppressed the growth of tumor cells. In RCC we found that low concentrations of MDA-7 (0.5-1.5 nM) suppressed growth without killing cells whereas higher levels of MDA-7 (> 20 nM) suppressed growth and enhanced cell death. Low levels of MDA-7 enhanced the sensitivity of RCCs to several agents that generate free radicals. The anti-proliferative and cytotoxic effects of MDA-7 and free radicals were not observed in primary renal cells. The mechanisms by which MDA-7 inhibits RCC proliferation and interacts with free radicals to kill RCCs are not fully understood.
Specific aim 1 will determine whether GST-MDA-7, in a dose-dependent fashion, causes increasing amounts of p38 MAPK activation and JNK1/2 activation, in RCCs, whose signaling is believed to be responsible for cytokine-induced apoptosis at high (> 30 nM) GST-MDA-7 concentrations. Additionally, we will prove or refute whether [arsenic trioxide (As2O3) and N-(4-hydroxyphenyl) retinamide (4-HPR)], agents that generate reactive oxygen species, enhance the ability of low GST-MDA-7 concentrations (0.5-1.5 nM) to cause prolonged activation of the p38 and JNK1/2 pathways.
Specific aim 2 will determine the mechanisms by which combined treatment of RCCs with PI3 kinase and MEK1/2 inhibitors enhance cell killing by purified MDA-7 protein. Additionally, we will prove or refute whether [arsenic trioxide (As2O3) and N-(4-hydroxyphenyl) retinamide (4-HPR)], agents that generate reactive oxygen species, enhance the lethality of low GST-MDA-7 concentrations by causing inactivation of ERK1/2.
Specific aim 3 will determine whether infusion of Ad.mda-7 or MDA-7 protein, into a pre-existing tumor, reduces RCC growth and enhances tumor sensitivity to As2O3 and 4-HPR. ? ?
| Menezes, Mitchell E; Bhoopathi, Praveen; Pradhan, Anjan K et al. (2018) Role of MDA-7/IL-24 a Multifunction Protein in Human Diseases. Adv Cancer Res 138:143-182 |
| Thomas, Shibu; Quinn, Bridget A; Das, Swadesh K et al. (2013) Targeting the Bcl-2 family for cancer therapy. Expert Opin Ther Targets 17:61-75 |
| Hamed, Hossein A; Das, Swadesh K; Sokhi, Upneet K et al. (2013) Combining histone deacetylase inhibitors with MDA-7/IL-24 enhances killing of renal carcinoma cells. Cancer Biol Ther 14:1039-49 |
| Das, Swadesh K; Sarkar, Siddik; Dash, Rupesh et al. (2012) Chapter One---Cancer terminator viruses and approaches for enhancing therapeutic outcomes. Adv Cancer Res 115:1-38 |
| Bareford, M Danielle; Park, Margaret A; Yacoub, Adly et al. (2011) Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells. Cancer Res 71:4955-67 |
| Park, Margaret A; Reinehr, Roland; Häussinger, Dieter et al. (2010) Sorafenib activates CD95 and promotes autophagy and cell death via Src family kinases in gastrointestinal tumor cells. Mol Cancer Ther 9:2220-31 |
| Sauane, Moira; Su, Zao-Zhong; Dash, Rupesh et al. (2010) Ceramide plays a prominent role in MDA-7/IL-24-induced cancer-specific apoptosis. J Cell Physiol 222:546-55 |
| Hamed, Hossein A; Yacoub, Adly; Park, Margaret A et al. (2010) OSU-03012 enhances Ad.7-induced GBM cell killing via ER stress and autophagy and by decreasing expression of mitochondrial protective proteins. Cancer Biol Ther 9:526-36 |
| Dent, Paul; Yacoub, Adly; Hamed, Hossein A et al. (2010) MDA-7/IL-24 as a cancer therapeutic: from bench to bedside. Anticancer Drugs 21:725-31 |
| Dent, Paul; Yacoub, Adly; Hamed, Hossein A et al. (2010) The development of MDA-7/IL-24 as a cancer therapeutic. Pharmacol Ther 128:375-84 |
Showing the most recent 10 out of 40 publications
