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Alantolactone induces G1 phase arrest and apoptosis of multiple myeloma cells and overcomes bortezomib resistance

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Abstract

Several sesquiterpene lactones have been extracted and demonstrated to exert various pharmacological functions in a variety of cancers. Here, we investigated anti-tumor effect of alantolactone, an allergenic sesquiterpene lactone, on human multiple myeloma (MM) and showed alantolactone inhibited growth of MM cells, both in the presence or absence of bone marrow (BM)-derived stromal cells (HS-5), and subsequent G1 phase arrest, and apoptosis as demonstrated by increased Annexin-V/7-AAD binding, caspase-3 or caspase-9 activation and down-modulation of activation of extracellular signal-regulated kinases 1/2. In addition, alantolactone reduced the secretion of MM survival and growth-related cytokines, vascular endothelial growth factor, from MM cells or HS-5 cells, and inhibited cytokine-induced osteoclastogenesis. Notably, alantolactone also inhibited cell proliferation in bortezomib-resistant MM cells. Taken together, alantolactone exerted anti-tumor effect on MM by suppressing cell proliferation, triggering apoptosis, partly damaging the BM microenvironment and overcoming proteasome inhibitor resistance, suggesting alantolactone may be a novel therapeutic approach for the treatment of human MM.

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Abbreviations

MM:

Multiple myeloma

ERK1/2:

Extracellular signal-regulated kinases1/2

VEGF:

Vascular endothelial growth factor

BM:

Bone marrow

IL-6:

Interleukin-6

b-FGF:

b-Fibroblast growth factor

HGF:

Hepatocyte growth factor

IGF-1:

Insulin-like growth factor-1

MEK:

Mitogen-activated protein kinases

CML:

Chronic myelogenous leukemia

TSP50:

Testes-specific protease 50

DMSO:

Dimethyl sulfoxide

PI:

Propidium iodide

RNase A:

Ribonuelease A

M-CSF:

Macrophage colony-stimulating factor

sRANK:

Soluble receptor activator of NFκB

ELISA:

Enzyme-linked immunosorbent assay

CDK:

Cyclin-dependent kinase

OC:

Osteoclast cell

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (81302034, 81272622).

Conflict of interest

The authors have no conflict of interest to declare.

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    Authors and Affiliations

    1. Department of Hematology, The Affiliated Hospital of Xuzhou Medical College, 99, West Huaihai Rd, Xuzhou, 221002, Jiangsu, China

      Yao Yao, Dandan Xia, Yueping Bian, Yueyue Sun, Feng Zhu, Bin Pan, Mingshan Niu, Kai Zhao, Qingyun Wu, Jianlin Qiao, Chunling Fu & Kailin Xu

    2. Blood Diseases Institute, Xuzhou Medical College, 84 West Huaihai Rd, Xuzhou, 221002, China

      Feng Zhu, Bin Pan, Qingyun Wu & Zhenyu Li

    3. Key Laboratory of Bone Marrow Stem Cell, Jiangsu Province, Xuzhou Medical College, 84 West Huaihai Rd, Xuzhou, 221002, China

      Yao Yao, Dandan Xia, Yueping Bian, Yueyue Sun, Mingshan Niu, Kai Zhao, Qingyun Wu, Jianlin Qiao & Chunling Fu

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    1. Yao Yao
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    Correspondence to Zhenyu Li or Kailin Xu.

    Additional information

    Yao Yao, Dandan Xia and Yueping Bian have contributed equally to this work.

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    Yao, Y., Xia, D., Bian, Y. et al. Alantolactone induces G1 phase arrest and apoptosis of multiple myeloma cells and overcomes bortezomib resistance. Apoptosis 20, 1122–1133 (2015). https://doi.org/10.1007/s10495-015-1140-2

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    • DOI: https://doi.org/10.1007/s10495-015-1140-2

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