Browse > Article
http://dx.doi.org/10.4014/jmb.1710.10063

Non-Benzoquinone Geldanamycin Analog, WK-88-1, Induces Apoptosis in Human Breast Cancer Cell Lines  

Zhao, Yu-Ru (School of Pharmacy, Bengbu Medical College)
Li, Hong-Mei (School of Pharmacy, Bengbu Medical College)
Zhu, Meilin (School of Pharmacy, Bengbu Medical College)
Li, Jing (School of Pharmacy, Bengbu Medical College)
Ma, Tao (School of Pharmacy, Bengbu Medical College)
Huo, Qiang (School of Pharmacy, Bengbu Medical College)
Hong, Young-Soo (Chemical Biology Research Center, KRIBB)
Wu, Cheng-Zhu (School of Pharmacy, Bengbu Medical College)
Publication Information
Journal of Microbiology and Biotechnology / v.28, no.4, 2018 , pp. 542-550 More about this Journal
Abstract
Heat shock protein 90 (Hsp90) is treated as a molecular therapeutic target for the prevention and treatment of cancer. Geldanamycin (GA) was the first identified natural Hsp90 inhibitor, but hepatotoxicity has limited its clinical application. Nevertheless, a new GA analog (WK-88-1) with the non-benzoquinone skeleton, obtained from genetically engineered Streptomyces hygroscopicus, was found to have anticancer activity against two human breast cancer cell lines. WK-88-1 produced concentration-dependent inhibition of cell proliferation, cell cycle arrest, and apoptosis in estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 cell lines. Detailed analysis showed that WK-88-1 downregulated some key cell cycle molecules (CDK1 and cyclin B1) and lead to $G_2/M$ cell cycle arrest. Further studies also showed that WK-88-1 could induce human breast cancer cell apoptosis by downregulating Hsp90 client proteins (Akt, p-Akt, IKK, c-Raf, and Bcl-2), decreasing the ATP level, increasing reactive oxygen species production, and lowering the mitochondrial membrane potential. Meanwhile, we discovered that WK-88-1 significantly decreased the levels of Her-2 and $ER-{\alpha}$ in MCF-7 cells but not in MDA-MB-231 cells. In addition, WK-88-1 significantly increased caspase-3, -8, and -9 activities and the cleavage of PARP in a concentration-dependent manner (with the exception of caspase-3 and PARP in MCF-7 cells). Taken together, our preliminary results suggest that WK-88-1 has the potential to play a role in breast cancer therapy.
Keywords
WK-88-1; non-benzoquinone geldanamycin analog; Hsp90; human breast cancer; apoptosis;
Citations & Related Records
Times Cited By KSCI : 2  (Citation Analysis)
연도 인용수 순위
1 Kim W, Lee JS, Lee D, Cai XF, Shin JC, Lee K, et al. 2007. Mutasynthesis of geldanamycin by the disruption of a gene producing starter unit: generation of structural diversity at the benzoquinone ring. Chembiochem 8: 1491-1494.   DOI
2 Shao FY, Du ZY, Ma DL, Chen WB, Fu WY, Ruan BB, et al. 2015. B5, a thioredoxin reductase inhibitor, induces apoptosis in human cervical cancer cells by suppressing the thioredoxin system, disrupting mitochondrion-dependent pathways and triggering autophagy. Oncotarget 6: 30939-30956.
3 Huang YC, Kuo CL, Lu KW, Lin JJ, Yang JL, Wu RS, et al. 2016. $18\alpha$-Glycyrrhetinic acid induces apoptosis of HL-60 human leukemia cells through caspases- and mitochondria-dependent signaling pathways. Molecules 21: 872.   DOI
4 Wang S, He M, Li L, Liang Z, Zou Z, Tao A. 2016. Cell-in-cell death is not restricted by caspase-3 defciency in MCF-7 cells. J. Breast Cancer 19: 231-241.   DOI
5 Jang WJ, Jung SK, Kang JS, Jeong JW, Bae MK, Joo SH, et al. 2014. Anti-tumor activity of WK88-1, a novel geldanamycin derivative, in gefitinib-resistant non-small cell lung cancers with Met amplification. Cancer Sci. 105: 1245-1253.   DOI
6 Hong YS, Jang WJ, Chun KS, Jeong CH. 2014. Hsp90 inhibition by WK88-1 potently suppresses the growth of geftinib-resistant H1975 cells harboring the T790M mutation in EGFR. Oncol. Rep. 31: 2619-2624.   DOI
7 Lee J, Shen P, Zhang G, Wu X, Zhang X. 2013. Dihydroartemisinin inhibits the Bcr/Abl oncogene at the mRNA level in chronic myeloid leukemia sensitive or resistant to imatinib. Biomed. Pharmacother. 67: 157-163.   DOI
8 Feng W, Cai D, Zhang B, Lou G, Zou X. 2015. Combination of HDAC inhibitors TSA and silibinin induces cell cycle arrest and apoptosis by targeting survivin and cyclinB1/Cdk1 in pancreatic cancer cells. Biomed. Pharmacother. 74: 257-264.   DOI
9 Elmore S. 2007. Apoptosis: a review of programmed cell death. Toxicol. Pathol. 35: 495-516.   DOI
10 Hsieh SC, Hsieh WJ, Chiang AN, Su NW, Yeh YT, Liao YC. 2016. The methanol-ethyl acetate partitioned fraction from Chinese olive fruits inhibits cancer cell proliferation and tumor growth by promoting apoptosis through the suppression of the $NF-{\kappa}B$ signaling pathway. Food Funct. 7: 4797-4803.   DOI
11 Wani ZA, Guru SK, Rao AV, Sharma S, Mahajan G, Behl A, et al. 2016. A novel quinazolinone chalcone derivative induces mitochondrial dependent apoptosis and inhibits PI3K/Akt/mTOR signaling pathway in human colon cancer HCT-116 cells. Food Chem. Toxicol. 87: 1-11.   DOI
12 Baichwal VR, Baeuerle PA. 1997. Activate $NF-{\kappa}B$ or die? Curr. Biol. 7: 94-96.   DOI
13 Fukuyo Y, Hunt CR, Horikoshi N. 2010. Geldanamycin and its anti-cancer activities. Cancer Lett. 290: 24-35.   DOI
14 Siegel RL, Miller KD, Jemal A. 2016. Cancer statistics. CA Cancer J. Clin. 66: 7-30.   DOI
15 Gonzalez-Angulo AM, Morales-Vasquez F, Hortobagyi GN. 2007. Overview of resistance to systemic therapy in patients with breast cancer. Adv. Exp. Med. Biol. 608: 1-22.
16 Schopf FH, Biebl MM, Buchner J. 2017. The Hsp90 chaperone machinery. Nat. Rev. Mol. Cell Biol. 18: 345-360.   DOI
17 Sankhala KK, Mita MM, Mita AC, Takimoto CH. 2011. Heat shock proteins: a potential anticancer target. Curr. Drug Targets 12: 2001-2008.   DOI
18 Sausville EA, Tomaszewski JE, Ivy P. 2003. Clinical development of 17-allylamino, 17-demethoxygeldanamycin. Curr. Cancer Drug Targets 3: 377-383.   DOI
19 Zhao Q, Wu CZ, Lee JK, Zhao SR, Li HM, Huo Q, et al. 2014. Anticancer effects of the Hsp90 inhibitor 17-demethoxy-reblastatin in human breast cancer MDA-MB-231 cells. J. Microbiol. Biotechnol. 24: 914-920.   DOI
20 Zhang Z, Li HM, Zhou C, Li Q, Ma L, Zhang Z, et al. 2016. Non-benzoquinone geldanamycin analogs trigger various forms of death in human breast cancer cells. J. Exp. Clin. Cancer Res. 35: 149.   DOI
21 Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. 2006. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem. Biol. Interact. 160: 1-40.   DOI
22 Itoh N, Semba S, Ito M, Takeda H, Kawata S, Yamakawa M. 2002. Phosphorylation of $Akt/P{\kappa}B$ is required for suppression of cancer cell apoptosis and tumor progression in human colorectal carcinoma. Cancer 94: 3127-3134.   DOI
23 Green DR, Reed JC. 1998. Mitochondria and apoptosis. Science 281: 1309-1312.   DOI
24 Ying J, Xu HD, Wu X. 2015. Emodin induces apoptosis of human osteosarcoma cells via mitochondria- and endoplasmic reticulum stress-related pathway. Int. J. Clin. Exp. Pathol. 8: 12837-12844.
25 Warburg OH. 2010. The classic: the chemical constitution of respiration ferment. Clin. Orthop. Relat. Res. 468: 2833-2839.   DOI
26 Chiang JH, Yang JS, Ma CY, Yang MD, Huang HY, Hsia TC, et al. 2011. Danthron, an anthraquinone derivative, induces DNA damage and caspase cascades-mediated apoptosis in SNU-1 human gastric cancer cells through mitochondrial permeability transition pores and Bax-triggered pathways. Chem. Res. Toxicol. 24: 20-29.   DOI
27 Cohen GM. 1997. Caspases: the executioners of apoptosis. Biochem. J. 326: 1-16.   DOI
28 Chiu CH, Chou YC, Lin JP, Kuo CL, Lu HF, Huang YP, et al. 2015. Chloroform extract of Solanum lyratum induced $G_0/G_1$ arrest via p21/p16 and induced apoptosis via reactive oxygen species, caspases and mitochondrial pathways in human oral cancer cell lines. Am. J. Chin. Med. 43: 1453-1469.   DOI
29 Kong GM, Tao WH, Diao YL, Fang PH, Wang JJ, Bo P, et al. 2016. Melittin induces human gastric cancer cell apoptosis via activation of mitochondrial pathway. World J. Gastroenterol. 22: 3186-3195.   DOI