Apoptosis is well recognized as an important biological process that controls cancer development and progression and the efficacy of chemotherapeutic drugs depends largely on their ability to induce apoptosis. Modern biology has suggested that cancer drug discovery based on molecular differences between tumor and normal cells is a feasible approach. Bcl-2, a critical anti-apoptotic protein, is overexpressed in the majority of malignancies and contributes to cancer development and drug resistance. Agents that target Bcl-2, therefore, offer a therapeutic advantage. Recently, we discovered a novel Nur77-Bcl-2 apoptotic pathway in cancer cells, in which orphan nuclear receptor Nur77 (also known as TR3) migrates from the nucleus to mitochondria where it interacts with Bcl-2 to induce cytochrome c release, which triggers apoptosis. Importantly, the interaction of Nur77 with Bcl-2 converts Bcl-2 from protector to killer, offering an opportunity to develop more effective anti-cancer agents. We hypothesize that peptides derived from the Bcl-2-binding region in Nur77 protein can be developed as therapeutic agents targeting Bcl-2-expressing cancer cells. In our preliminary studies, we found that a cell-permeable peptide with 9 amino acid residues from the Nur77 protein effectively induces apoptosis of cancer cells in vitro and in animals. The peptide, like Nur77, targets mitochondria through its interaction with Bcl-2 and induces Bcl-2 conformational change. In this STTR Phase I application, we propose to improve the pharmacological and biopharmaceutical properties by modifying the lead Nur77 peptide. Our goal will be accomplished by 3 aims: (1). Design and synthesis of Nur77 peptides using amino acid substitution and conjugation with a tumor selective homing peptide; (2). Evaluate Nur77 peptides for their mitochondrial targeting, Bcl-2 interaction, conformational change, and apoptosis induction; (3). Evaluate Nur77 peptides for their pharmacokinetics, tolerability in mice and in vivo efficacy. Our goal is to identify a stable, tumor-selective, cell-permeable peptide with minimal toxicity and suitable pharmacokinetics for Phase II development and commercialization. ? ? ?
| Kolluri, Siva Kumar; Zhu, Xiuwen; Zhou, Xin et al. (2008) A short Nur77-derived peptide converts Bcl-2 from a protector to a killer. Cancer Cell 14:285-98 |
