Calmodulin antagonists induce cell cycle arrest and apoptosis in vitro and inhibit tumor growth in vivo in human multiple myeloma
| Autor: | Saki Yurimoto, Osamu Imataki, Takuya Matsunaga, Hiroaki Dobashi, Akihito Matsuoka, Shigeyuki Yokokura, Shuji Bandoh |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Cell cycle checkpoint Apoptosis Antineoplastic Agents Cell cycle Pharmacology Calcium in biology Flow cytometry Mice Calmodulin Multiple myeloma In vivo Cell Line Tumor Genetics medicine Animals Humans Calcium Signaling Cell Proliferation Mice Inbred BALB C medicine.diagnostic_test Cell growth business.industry Cell Cycle Checkpoints Xenograft Model Antitumor Assays Oncology Cell culture Cancer research Female business Research Article |
| Zdroj: | BMC Cancer |
| ISSN: | 1471-2407 |
| DOI: | 10.1186/1471-2407-14-882 |
| Popis: | Background Human multiple myeloma (MM) is an incurable hematological malignancy for which novel therapeutic agents are needed. Calmodulin (CaM) antagonists have been reported to induce apoptosis and inhibit tumor cell invasion and metastasis in various tumor models. However, the antitumor effects of CaM antagonists on MM are poorly understood. In this study, we investigated the antitumor effects of naphthalenesulfonamide derivative selective CaM antagonists W-7 and W-13 on MM cell lines both in vitro and in vivo. Methods The proliferative ability was analyzed by the WST-8 assay. Cell cycle was evaluated by flow cytometry after staining of cells with PI. Apoptosis was quantified by flow cytometry after double-staining of cells by Annexin-V/PI. Molecular changes of cell cycle and apoptosis were determined by Western blot. Intracellular calcium levels and mitochondrial membrane potentials were determined using Fluo-4/AM dye and JC-10 dye, respectively. Moreover, we examined the in vivo anti-MM effects of CaM antagonists using a murine xenograft model of the human MM cell line. Results Treatment with W-7 and W-13 resulted in the dose-dependent inhibition of cell proliferation in various MM cell lines. W-7 and W-13 induced G1 phase cell cycle arrest by downregulating cyclins and upregulating p21cip1. In addition, W-7 and W-13 induced apoptosis via caspase activation; this occurred partly through the elevation of intracellular calcium levels and mitochondrial membrane potential depolarization and through inhibition of the STAT3 phosphorylation and subsequent downregulation of Mcl-1 protein. In tumor xenograft mouse models, tumor growth rates in CaM antagonist-treated groups were significantly reduced compared with those in the vehicle-treated groups. Conclusions Our results demonstrate that CaM antagonists induce cell cycle arrest, induce apoptosis via caspase activation, and inhibit tumor growth in a murine MM model and raise the possibility that inhibition of CaM might be a useful therapeutic strategy for the treatment of MM. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|