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Background: Background: Despite the promising clinical potential of bone morphogenetic protein (BMP)-related therapies for bone formation, their side effects warrant the need for alternative therapeutic peptides. BMP family members can aid in bone repair; however, peptides derived from BMP2/4 have not yet been investigated. Methods: In this study, three candidates BMP2/4 consensus peptide (BCP) 1, 2, and 3 were identified and their ability to induce osteogenesis in C2C12 cells was analyzed. First, an alkaline phosphatase (ALP) staining assay was performed to evaluate the osteogenic effects of BCPs. Next, the effects of BCPs on RNA expression levels and protein abundances of osteogenic markers were explored. Furthermore, the transcriptional activity of ALP by BCP1 and in silico molecular docking model on BMP type IA receptor (BRIA) were performed. Results: BCP1-3 induced higher RUNX2 expression than BMP2. Interestingly, among them, BCP1 significantly promoted osteoblast differentiation more than BMP2 in ALP staining with no cytotoxicity. BCP1 significantly induced the osteoblast markers, and the highest RUNX2 expression was observed at 100 ng/mL compared to other concentrations. In transfection experiments, BCP1 stimulated osteoblast differentiation via RUNX2 activation and the Smad signaling pathway. Finally, in silico molecular docking suggested the possible binding sites of BCP1 on BRIA. Conclusion: These results show that BCP1 promotes osteogenicity in C2C12 cells. This study suggests that BCP1 is the most promising candidate peptide to replace BMP2 for osteoblast differentiation.

Reactive oxygen species have been considered as a therapeutic target for cancer treatment. In this study, we characterized the anticancer activity of novel small molecule inhibitor of cytochrome bc1, HIF-143, in pancreatic cancer. HIF-143 shares common structural moiety with known cytochrome bc1 Qo inhibitors including azoxystrobin and E-α-methoxyacrylate-stilbene. HIF-143 inhibits reduction of cytochrome c by purified mitochondria in the presence of rotenone and induction of reactive oxygen species by hypoxia or epidermal growth factor in cellular context. HIF-143 also suppresses activation of EGFR and downstream ERK and AKT induced by EGF treatment. EGF-induced transcription was also inhibited by HIF-143. Interestingly, these effects were synergistic when combined with EGFR inhibitor such as Erlotinib and Gefitinib. Cell proliferation, survival, and anchorage-independent growth were also synergistically inhibited by HIF-143 and Erlotinib. HIF-143 also inhibited pancreatic tumor growth in BxPC-3 human pancreatic cancer xenograft model. The inhibition of tumor growth was much higher when animals were treated with both HIF-143 and Erlotinib than individual treatment, suggesting synergistic anticancer activity in vivo. In addition, when HIF-143 was combined with Erlotinib and Gemcitabine, anticancer efficacy was increased without the increase of sign of toxicity, showing addition of HIF-143 can give clinical benefit to pancreatic cancer patients. Toxicological study showed that combination of HIF-143 and Erlotinib is safe enough with safety margin higher than 6-fold. These findings suggest that pharmacological targeting of complex III might be a promising approach to treat pancreatic cancer. These results provide scientific rational for testing of HIF-143 in the clinical trial to develop as a novel anticancer drug. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3841. doi:1538-7445.AM2012-3841