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Apoptosis

, Volume 20, Issue 8, pp 1122–1133 | Cite as

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

  • Yao Yao
  • Dandan Xia
  • Yueping Bian
  • Yueyue Sun
  • Feng Zhu
  • Bin Pan
  • Mingshan Niu
  • Kai Zhao
  • Qingyun Wu
  • Jianlin Qiao
  • Chunling Fu
  • Zhenyu LiEmail author
  • Kailin XuEmail author
Original Paper

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.

Keywords

Alantolactone Multiple myeloma Cytotoxicity Bortezomib resistance ERK1/2 

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

Notes

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.

Supplementary material

10495_2015_1140_MOESM1_ESM.docx (4.3 mb)
Supplementary material 1 (DOCX 4374 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of HematologyThe Affiliated Hospital of Xuzhou Medical CollegeXuzhouChina
  2. 2.Blood Diseases InstituteXuzhou Medical CollegeXuzhouChina
  3. 3.Key Laboratory of Bone Marrow Stem Cell, Jiangsu ProvinceXuzhou Medical CollegeXuzhouChina

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