Abstract
Cucurbitacin B (CuB), a triterpenoid compound isolated from the stems of Cucumis melo, has long been used to treat hepatitis and hepatoma in China. Although its remarkable anti-cancer activities have been reported, the mechanism by which it achieves this therapeutic activity remains unclear. This study was designed to investigate the molecular mechanisms by which CuB inhibits cancer cell proliferation. Our results indicate that CuB is a novel inhibitor of Aurora A in multiple myeloma (MM) cells, arresting cells in the G2/M phase. CuB also inhibited IL-10-induced STAT3 phosphorylation, synergistically increasing the anti-tumor activity of Adriamycin in vitro. CuB induced dephosphorylation of cofilin, resulting in the loss of mitochondrial membrane potential, release of cytochrome c, and activation of caspase-8. CuB inhibited MM tumor growth in a murine MM model, without host toxicity. In conclusion, these results indicate that CuB interferes with multiple cellular pathways in MM cells. CuB thus represents a promising therapeutic tool for the treatment of MM.
Highlights
Multiple myeloma (MM) is a malignant clonal plasma disorder characterized by damage to multiple organs including bone lesions, hypocalcemia, anemia, and renal insufficiency [1]
In order to investigate synergy of Cucurbitacin B (CuB) and Adriamycin, cells were incubated with both CuB (0, 25, 50, 100 and 200 nM) and Adriamycin (0, 25, 50, 100 and 200 nM) in a checkerboard fashion
Proliferation of MM1.S, MM1.R and U266 cells was substantially inhibited in the presence of 50, 100 and 200 nM CuB and Adriamycin, while 50 nM Adriamycin alone did not exert significantly antiproliferative activity
Summary
Multiple myeloma (MM) is a malignant clonal plasma disorder characterized by damage to multiple organs including bone lesions, hypocalcemia, anemia, and renal insufficiency [1]. CuB and related compounds have been shown to exert www.impactjournals.com/oncotarget anticancer activity in in vitro and in vivo models, of hepatoma [6], colorectal cancer [7], breast cancer [8], neuroblastoma [9], myeloid leukemia [10], pancreatic cancer [11], lung cancer [12], and melanoma [13] These promising results prompted us to evaluate the possibility of using CuB to treat MM, either alone or in combination with current chemotherapeutic agents, to improve response rates and reduce toxicity
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