Research of reversal effect of PESV on multi-drug resistance of leukemia stem cell

YANG Xiang-dong1 WANG Xing-li1 YANG Wen-hua1 ZHAO Lei1 YAN Tian-gai1

(1.First Teaching Hospital of Tianjin University of TCM, Tianjin, China 300381)

【Abstract】The BALB/c mouse models with multidrug-resistant (MDR) leukemia were applied in the study to observe the effects of peptide extract from scorpion venom (PESV) on the upstream signal factors of P-gp in the leukemia stem cell (LSC), and to study the mechanism of PESV in reversing the MDR of LSC. At the same time, the expression levels of P-gp, MDR1 mRNA and PI3-K, NF-κB were respectively detected by flow cytometry, RT-PCR, Western blot and Elisa, and the histopathological methods were used to examine the mouse liver and spleen. The results of the experiment were as follows: mice of the control group didn’t show any obvious change, while those in the other six groups all showed such symptoms as arched back and emaciation. The liver was enlarged, and inflammation and necrosis were found in all liver tissue. The expression levels of P-gp and PI3 K on the LSC membrane of mouse tumor were down-regulated; The expression level of MDR1 mRNA in the cytoplasm was obviously down-regulated in the low-dose PESV group, while they were up-regulated in the middle-dose group and the high-dose group to different degrees. The expression level of NF-κB in the cell nucleus of LSC was remarkably decreased. PESV played an outstanding role in down-regulating PI3K/NF-κB/MDR1 at the upstream region of P-gp, and it could enhance the sensitivity of LSCs to ADM to a certain degree. Therefore, this experiment explained one of the possible mechanisms of PESV in reversing MDR of LSCs, thus providing the foundation for further study on combinational anti-cancer effects of PESV.

【Keywords】 peptide extract from scorpion venom (PESV) ; multi-drug resistance (MDR); BALB/c mouse model; upstream signal factors of P-gp;

【DOI】

【Funds】 Project Supported by Science and Technology Commission of Tianjin Municipality (12JCQNJC09000)

Download this article

(Translated by WU XX)

    References

    [1] Mattern J, Volm M.Multiple pathway drug-resistance (review) [J]. Int J Oncol, 1993, 2 (4): 557.

    [2] O saki M, O shinura M, Ito H. P13K-Akt pathway its functions and alterations in human cancer [J]. Apoptosis, 2004, 9 (6): 667.

    [3] Juliano R L, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants [J]. Biochem Biophys Acta, 1976, 455 (1): 152.

    [4] Yang XD, Li HY, Li DG. 蝎毒多肽对白血病细胞株KG1a干细胞活性的影响 [J]. China Journal of Traditional Chinese Medicine and Pharmacy, 2015, 30 (4): 101 (in Chinese).

    [5] Cheng ZY, Li L, Wang YL, et al. Role of PTEN gene in multidrug resistance reversal in leukemia cells [J]. Academic Journal of Second Military Medical University, 2013, 34 (2): 142 (in Chinese).

    [6] Luan FJ, Yang CZ, Ma JG, et al. 一株人红白血病多药耐药细胞系 (K562/AO2) 的建立及其耐药特性的研究 [J]. Chinese Journal of Oncology, 1993, 15: 101 (in Chinese).

    [7] Hao Z, Yang WH. Study of molecular mechanism on PESV in inhibiting acute leukemic cell extramedullary infiltration and transmutation [J]. China Journal of Traditional Chinese Medicine and Pharmacy. 2012, 27 (4): 1106 (in Chinese).

    [8] Xu Yan, Zhi Feng, Xu Guangming, et al. Overcoming multidrugresistance in vitro and in vivo using the novel P-glycoprotein inhibitor 1416 [J]. Biosci Rep, 2012 (32): 559.

    [9] Zunino S J, Storms D H, Ducore J M. Novel in vivo model of inducible multi-drug resistance in acute lymphoblastic leukemia with chromosomal translocation t (4;11) [J]. Cancer Lett, 2010, 296 (1): 49.

    [10] Perrin L, Gatouillat G, Balasse E, et al. lnduction of autoantibodies to murine P glycoprotein: consequences on drug sensitivity in MDR cancer cells and on the expression of MDR genes [J]. Biochem Biophys Res Commun, 2007, 358 (1): 325.

    [11] Tian K, Wang Y, Huang Y. Methylation of WTH3, a possible drug resistant gene, inhibits p53 regulated expression [J]. BMC Cancer, 2008, 8: 327.

    [12] Mackay H J, Eisenhauer E A, Kamel-Reid S, et al. Molecular determinantks of outcome with mammalian target of rapamycin inhibition in endometrial cancer [J]. Cancer, 2013, 25 (3): 123.

    [13] LI JW, HU J, ZHAGN GR, et al. Effects of anti-cancer peptide fraction III from Buthus Martensii Karsch on apoptosis of human liver cancer cells [J]. Journal of Jilin University (Medicine Edition), 2006, 32 (4): 625 (in Chinese).

    [14] Qin BN, Teng WJ, Liu RJ, et al. 大黄蛰虫丸对慢性粒细胞白血病K562细胞增殖凋亡及PI3K/AKT信号传导通路的影响 [J]. Lishizhen Medicine and Materia Medica Research, 2015, 26 (3): 522 (in Chinese).

    [15] Xin M, Chen J, Guo YH. Effects of isoflavones on apoptosis and pi3k/akt signaling pathway in bladder cancer cells [J]. Guangdong Medical Journal, 2015, 36 (5): 690 (in Chinese).

This Article

ISSN:1001-5302

CN: 11-2272/R

Vol 41, No. 24, Pages 4648-4653

December 2016

Downloads:0

Share
Article Outline

Abstract

  • 1 Materials
  • 2 Methods
  • 3 Results
  • 4 Discussions
  • References