Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Effect of Hsp90 Inhibitor KW-2478 on HepG2 Cells

Author(s): Xiaomin Chang, Xuerong Zhao, Jianping Wang, Shi Ding, Lijun Xiao*, Enhong Zhao and Xin Zheng

Volume 19, Issue 18, 2019

Page: [2231 - 2242] Pages: 12

DOI: 10.2174/1871520619666191023094610

Price: $65

Abstract

Objective: The objectives of this study were to investigate the effects of proliferation, apoptosis, cell cycle, invasion, and senescence of KW-2478 on HepG2 cells, and to explore the related mechanism of apoptosis and the cell cycle.

Methods: HepG2 cells (hepatocellular carcinoma cells) were cultured with KW-2478, at different doses and for different times, in vitro. The MTT assay was used to detect the effect of KW-2478 on proliferation of HepG2 cells. Flow cytometry was used to determine the effects of KW-2478 on the cell cycle and apoptosis of HepG2 cells. The Transwell assay was used to determine the effect of KW-2478 on cell invasion. The β-galactosidase assay tested the effect of low-dose KW-2478 on the senescence of HepG2 cells. Western blotting and the quantitative polymerase chain reaction were used respectively to assess changes in protein and mRNA levels of related factors in HepG2 cells after the KW-2478 treatment.

Results: KW-2478 significantly inhibited proliferation of HepG2 cells. KW-2478 induced apoptosis and cell cycle arrest of HepG2 cells, and inhibited the invasion of HepG2 cells; low dose KW-2478 promoted HepG2 senescence.

Conclusion: KW-2478 inhibited the proliferation of HepG2 cells, induced apoptosis and cell cycle arrest, inhibited invasion, and promoted senescence. KW-2478 affected the expression of related factors in the mitochondrial apoptotic signaling and cell cycle-related regulatory pathways. KW-2478 downregulated the expression of STAT3, which is a key factor in the JAK-STAT pathway, indicating that KW-2478 may affect the function of HepG2 cells by downregulating STAT3.

Keywords: KW-2478, HepG2, proliferation, apoptosis, cell cycle, invasion, senescence.

« Previous Next »
Graphical Abstract

[1]
Fitzmaurice, C.; Dicker, D.; Pain, A.; Hamavid, H.; Moradi-Lakeh, M.; MacIntyre, M.F.; Allen, C.; Hansen, G.; Woodbrook, R.; Wolfe, C.; Hamadeh, R.R.; Moore, A.; Werdecker, A.; Gessner, B.D.; Te Ao, B.; McMahon, B.; Karimkhani, C.; Yu, C.; Cooke, G.S.; Schwebel, D.C.; Carpenter, D.O.; Pereira, D.M.; Nash, D.; Kazi, D.S.; De Leo, D.; Plass, D.; Ukwaja, K.N.; Thurston, G.D.; Yun Jin, K. Simard, E.P.; Mills, E.; Park, E.K.; Catalá-López, F.; deVeber, G.; Gotay, C.; Khan, G.; Hosgood, H.D., III; Santos, I.S.; Leasher, J.L.; Singh, J.; Leigh, J.; Jonas, J.B.; Sanabria, J.; Beardsley, J.; Jacobsen, K.H.; Takahashi, K.; Franklin, R.C.; Ronfani, L.; Montico, M.; Naldi, L.; Tonelli, M.; Geleijnse, J.; Petzold, M.; Shrime, M.G.; Younis, M.; Yonemoto, N.; Breitborde, N.; Yip, P.; Pourmalek, F.; Lotufo, P.A.; Esteghamati, A.; Hankey, G.J.; Ali, R.; Lunevicius, R.; Malekzadeh, R.; Dellavalle, R.; Weintraub, R.; Lucas, R.; Hay, R.; Rojas-Rueda, D.; Westerman, R.; Sepanlou, S.G.; Nolte, S.; Patten, S.; Weichenthal, S.; Abera, S.F.; Fereshtehnejad, S.M.; Shiue, I.; Driscoll, T.; Vasankari, T.; Alsharif, U.; Rahimi-Movaghar, V.; Vlassov, V.V.; Marcenes, W.S.; Mekonnen, W.; Melaku, Y.A.; Yano, Y.; Artaman, A.; Campos, I.; MacLachlan, J.; Mueller, U.; Kim, D.; Trillini, M.; Eshrati, B.; Williams, H.C.; Shibuya, K.; Dandona, R.; Murthy, K.; Cowie, B.; Amare, A.T.; Antonio, C.A.; Castañeda-Orjuela, C.; van Gool, C.H.; Violante, F.; Oh, I.H.; Deribe, K.; Soreide, K.; Knibbs, L.; Kereselidze, M.; Green, M.; Cardenas, R.; Roy, N.; Tillmann, T.; Li, Y.; Krueger, H.; Monasta, L.; Dey, S.; Sheikhbahaei, S.; Hafezi-Nejad, N.; Kumar, G.A.; Sreeramareddy, C.T.; Dandona, L.; Wang, H.; Vollset, S.E.; Mokdad, A.; Salomon, J.A.; Lozano, R.; Vos, T.; Forouzanfar, M.; Lopez, A.; Murray, C.; Naghavi, M. Global Burden of Disease Cancer Collaboration. The global burden of cancer 2013. JAMA Oncol., 2015, 1(4), 505-527.
[http://dx.doi.org/10.1001/jamaoncol.2015.0735] [PMID: 26181261]
[2]
Soga, S.; Akinaga, S.; Shiotsu, Y. Hsp90 inhibitors as anti-cancer agents, from basic discoveries to clinical development. Curr. Pharm. Des., 2013, 19(3), 366-376.
[http://dx.doi.org/10.2174/138161213804143617] [PMID: 22920907]
[3]
Nakashima, T.; Ishii, T.; Tagaya, H.; Seike, T.; Nakagawa, H.; Kanda, Y.; Akinaga, S.; Soga, S.; Shiotsu, Y. New molecular and biological mechanism of antitumor activities of KW-2478, a novel nonansamycin heat shock protein 90 inhibitor, in multiple myeloma cells. Clin. Cancer Res., 2010, 16(10), 2792-2802.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-3112] [PMID: 20406843]
[4]
Ishii, T.; Seike, T.; Nakashima, T.; Juliger, S.; Maharaj, L.; Soga, S.; Akinaga, S.; Cavenagh, J.; Joel, S.; Shiotsu, Y. Anti-tumor activity against multiple myeloma by combination of KW-2478, an Hsp90 inhibitor, with bortezomib. Blood Cancer J., 2012, 2(4)e68
[http://dx.doi.org/10.1038/bcj.2012.13] [PMID: 22829970]
[5]
Supko, J.G.; Hickman, R.L.; Grever, M.R.; Malspeis, L. Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother. Pharmacol., 1995, 36(4), 305-315.
[http://dx.doi.org/10.1007/BF00689048] [PMID: 7628050]
[6]
Ferrarini, M.; Heltai, S.; Zocchi, M.R.; Rugarli, C. Unusual expression and localization of heat-shock proteins in human tumor cells. Int. J. Cancer, 1992, 51(4), 613-619.
[http://dx.doi.org/10.1002/ijc.2910510418] [PMID: 1601523]
[7]
Li, P.; Nijhawan, D.; Budihardjo, I.; Srinivasula, S.M.; Ahmad, M.; Alnemri, E.S.; Wang, X. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell, 1997, 91(4), 479-489.
[http://dx.doi.org/10.1016/S0092-8674(00)80434-1] [PMID: 9390557]
[8]
Youle, R.J.; Strasser, A. The BCL-2 protein family: Opposing activities that mediate cell death. Nat. Rev. Mol. Cell Biol., 2008, 9(1), 47-59.
[http://dx.doi.org/10.1038/nrm2308] [PMID: 18097445]
[9]
Ashkenazi, A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat. Rev. Cancer, 2002, 2(6), 420-430.
[http://dx.doi.org/10.1038/nrc821] [PMID: 12189384]
[10]
Parrish, A.B.; Freel, C.D.; Kornbluth, S. Cellular mechanisms controlling caspase activation and function. Cold Spring Harb. Perspect. Biol., 2013, 5(6)a008672
[http://dx.doi.org/10.1101/cshperspect.a008672] [PMID: 23732469]
[11]
Su, C. Survivin in survival of hepatocellular carcinoma. Cancer Lett., 2016, 379(2), 184-190.
[http://dx.doi.org/10.1016/j.canlet.2015.06.016] [PMID: 26118774]
[12]
Schmidt, M.; Rohe, A.; Platzer, C.; Najjar, A.; Erdmann, F.; Sippl, W. Regulation of G2/M Transition by inhibition of WEE1 and PKMYT1 kinases. Molecules, 2017, 22(12)E2045
[http://dx.doi.org/10.3390/molecules22122045] [PMID: 29168755]
[13]
Zhu, M.H.; Ni, C.R.; Zhu, Z.; Li, F.M.; Zhang, S.M. Immunohistochemical demonstration of cyclins A, B, D1, D3 and E in hepatocellular carcinomas using tissue microarrays. Zhonghua Bing Li Xue Za Zhi, 2003, 32(5), 440-443.
[PMID: 14633457]
[14]
Eilers, M.; Schirm, S.; Bishop, J.M. The MYC protein activates transcription of the alpha-prothymosin gene. EMBO J., 1991, 10(1), 133-141.
[http://dx.doi.org/10.1002/j.1460-2075.1991.tb07929.x] [PMID: 1989881]
[15]
Kleiner, D.E.; William, G.; Stetler-Stevenson, W.G. Matrix metalloproteinases and metastasis. Cancer Chemother. Pharmacol., 1999, 43(Suppl. l), S42-S51.
[http://dx.doi.org/10.1007/s002800051097]
[16]
Saiki, I.; Fujii, H.; Yoneda, J.; Abe, F.; Nakajima, M.; Tsuruo, T.; Azuma, I. Role of aminopeptidase N (CD13) in tumor-cell invasion and extracellular matrix degradation. Int. J. Cancer, 1993, 54(1), 137-143.
[http://dx.doi.org/10.1002/ijc.2910540122] [PMID: 8097496]
[17]
Hayflick, L.L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res., 1965, 37, 614-636.
[http://dx.doi.org/10.1016/0014-4827(65)90211-9] [PMID: 14315085]
[18]
Turinetto, V.; Vitale, E.; Giachino, C. Senescence in human mesenchymal stem cells: Functional changes and implications in stem cell-based therapy. Int. J. Mol. Sci., 2016, 17(7)E1164
[http://dx.doi.org/10.3390/ijms17071164] [PMID: 27447618]
[19]
Schmitt, C.A. Cellular senescence and cancer treatment. Biochim. Biophys. Acta, 2007, 1775(1), 5-20.
[PMID: 17027159]
[20]
Frank, D.A. STAT3 as a central mediator of neoplastic cellular transformation. Cancer Lett., 2007, 251(2), 199-210.
[http://dx.doi.org/10.1016/j.canlet.2006.10.017] [PMID: 17129668]
[21]
Qin, A.C.; Yu, Q.; Gao, Y. Inhibition of STAT3/cyclinD1 pathway promotes chemotherapeutic sensitivity of colorectal cancer. Biochem. Biophys. Res. Commun., 2015, 4(457), 681-687.
[22]
Fuke, H.; Shiraki, K.; Sugimoto, K.; Tanaka, J.; Beppu, T.; Yoneda, K.; Yamamoto, N.; Ito, K.; Masuya, M.; Takei, Y. Jak inhibitor induces S phase cell-cycle arrest and augments TRAIL-induced apoptosis in human hepatocellular carcinoma cells. Biochem. Biophys. Res. Commun., 2007, 363(3), 738-744.
[http://dx.doi.org/10.1016/j.bbrc.2007.09.049] [PMID: 17904524]
[23]
Sánchez, A.; Nagy, P.; Thorgeirsson, S.S. STAT-3 activity in chemically-induced hepatocellular carcinoma. Eur. J. Cancer, 2003, 39(14), 2093-2098.
[http://dx.doi.org/10.1016/S0959-8049(03)00393-9] [PMID: 12957465]

Rights & Permissions Print Cite
Article Metrics
35
5
© 2024 Bentham Science Publishers | Privacy Policy