In conclusion, distinct solid tumor cells secrete GRP-78 thereby gaining resistance to bortezomib. These Selleckchem Baf-A1 findings describe a hitherto unknown mechanism of resistance to proteasome inhibitors and may offer a novel strategy to increase
the susceptibility of solid tumor cells to bortezomib. Poster No. 154 The Effect of Platycodin D on Breast Cancer-Induced Bone Destruction Sun Kyoung Lee 1,2 , Kwang-Kyun Park1,2, Yeong-Shik Kim3, Young-Wan Ha3, Won-Yoon Chung1,2 1 Department of Oral Biology, Oral Cancer Research Institute, Oral Science Research Institute, Brain Korea 21 Project, College of Dentistry Yonsei University, Seoul, Korea Republic, 2 Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, Korea Republic, 3 Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, Korea Republic Breast cancer is the most common cancer
affecting women in the MLL inhibitor United States and other countries. In individuals with breast cancer, the frequency of bone metastasis is much higher than other organ metastases. Breast cancer cells secrete osteolytic factors, such as parathyroid hormone-related protein (PTHrP), interleukin (IL)-1β, -6 and -11. These factors stimulate stromal/osteoblastic cells to over-express receptor activator of nuclear factor-kappa B ligand (RANKL), which is required to induce osteoclast www.selleckchem.com/products/VX-680(MK-0457).html formation/activation. Over-expression of RANKL results in increased osteoclast formation and bone resorption. The subsequent bone resorption induces the release of various growth factors from the bone matrix, such as transforming growth factor (TGF)-β, insulin-like growth
factor selleck screening library (IGF)-Iand -II. The released growth factors stimulate the proliferation of cancer cells. The interaction between tumor cells and bone cells, called to ‘vicious cycle’, is crucial for the initiation and promotion of skeletal metastasis. We found that platycodin D (PD), a major constituent of triterpene saponins found in the root of Platycodon grandiflorum, inhibited the viability of human breast cancer MDA-MB-231 cells, in a dose-dependent manner. However, PD did not influence the secretion of osteolytic factors in MDA-MB-231 cells and RANKL/OPG ratio in osteoblasts treated with conditioned media of MDA-MB-231 cells. PD suppressed RANKL-induced osteoclast formation/activation through down-regulation of c-Fos and nuclear factor of activated T cells 1 (NFATc1) in mouse bone marrow-derived macrophage (BMM) cells. PD also induced apoptosis in osteoclasts. Consistent with the in vitro effect, PD showed the inhibitory effect on tumor growth and tumor-induced bone destruction in vivo.
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