Polyphyllin I induces cell cycle arrest and apoptosis in human myeloma cells via modulating β-catenin signaling pathway

Abstract

Multiple myeloma (MM) is an indolent B-cell disease characterized by clonal proliferation of malignant plasma cells. Multiple myeloma remains incurable despite new targeted drugs and development of drug resistance or intolerable toxicity emerges as a major problem. Therefore, design, identification, and validation of novel chemicals with therapeutic potential are clearly needed for MM treatment. Here, we explore polyphyllin I (PPI), a major active constituent extracted from Paris polyphyllin, its inhibitory effects and its mechanisms in MM cells in vitro. We found that PPI inhibited the proliferation of myeloma cells. The combination of PPI with dexamethasone, doxorubicin, arsenic trioxide, or bortezomib enhanced the inhibition of cell growth. As analyzed by flow cytometry, MM cells were arrested at G2/M phase and apoptotic cells increased in a time-dependent manner. Morphological changes of cells undergoing apoptosis were observed under light microscope. To explore the mechanism of apoptosis induced by PPI, we next examined whether the Wingless-Int (Wnt)/β-catenin signaling pathway played a role in the PPI-induced growth inhibition in MM cells. The canonical Wnt signaling pathway is activated in MM cells through constitutively active β-catenin, a messenger molecule relevant to growth, survival, and migration of MM cells. Western blotting was used to measure the protein levels of β-catenin, and PPI treatment led to downregulating the expression of β-catenin protein and was followed by inhibition of β-catenin nuclear localization. As a result, β-catenin downstream targets, such as cyclin D1 and survivin, were downregulated. To the best of our knowledge, this is the first report identifying anti-proliferative potency of PPI against myeloma cells. PPI blocks β-catenin nuclear translocation and decreasing expression of the downstream targets of β-catenin. Our results suggest that PPI is a novel inhibitor of β-catenin activity with potential anti-myeloma efficacy.

Keywords: apoptosis; multiple myeloma; polyphyllin I; β-catenin.