Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

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

Combined Treatment with JFKD and Gefitinib Overcomes Drug Resistance in Non-Small Cell Lung Cancer

Author(s): Xiaoming Huang, Jingchun Sun and Jianli Sun*

Volume 22, Issue 3, 2021

Published on: 19 August, 2020

Page: [389 - 399] Pages: 11

DOI: 10.2174/1389201021999200819105209

Price: $65

Abstract

Background: Gefitinib is an important drug used to treat Non-Small Cell Lung Cancer (NSCLC) with EGFR activating mutations, but drug resistance restricts its clinical application. In this present study, combined Jin Fu Kang Decoction (JFKD) and gefitinib showed specific cytotoxicity to gefitinib-resistant cancer cells (PC-9/gef).

Objective: This study aimed to decipher the molecular mechanism of the JFKD on drug resistance when used together with Gefitinib and to find the contributing bio-active substance(s) in JFKD based on the putative mechanism.

Methods: To investigate the combined effect of gefitinib and JFKD, in vitro experiments were conducted on the established gefitinib-resistant PC-9 subclone, while in vivo experiments were conducted on the BALB/c nude mice with PC-9/gef xenografts. Western blot was used to evaluate the protein expression, and Ultra-Performance Liquid Chromatography (UPLC) coupled with quadrupole time-offlight Mass Spectrometry (MS) was used to detect the bio-active compounds of JFKD.

Results: The expression of the PTEN-relevant protein p-EGFR, p-Akt in vitro was inhibited more when combined JKFD and gefitinib were used, whereas the activities of PDCD4 and PTEN were increased; remarkably, in vivo experiments showed enhanced tumor growth inhibition when treated with this combination. Due to this combination, the effect on the gefitinib-resistant cell line, one of the JFKD-induced anti-cancer mechanisms, was found. To link the putative mechanism and the anticancer compounds in JFKD, 14 saponins and flavonoids were detected.

Conclusion: The results suggested that a promising TCM-participated therapy can be established by the putative mechanism of the combined treatment in resistant NSCLC and screening the contributing bio-active substance(s) in JFKD is meaningful on new TCM formula discovery.

Keywords: Jin Fu Kang decoction, Gefitinib, acquired drug resistance, non-small cell lung cancer, EGFR pathway, UPLC-MS.

« Previous Next »
Graphical Abstract

[1]
Ferlay, J.; Shin, H-R.; Bray, F.; Forman, D.; Mathers, C.; Parkin, D.M. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer, 2010, 127(12), 2893-2917.
[http://dx.doi.org/10.1002/ijc.25516] [PMID: 21351269]
[2]
Ohe, Y.; Ohashi, Y.; Kubota, K.; Tamura, T.; Nakagawa, K.; Negoro, S.; Nishiwaki, Y.; Saijo, N.; Ariyoshi, Y.; Fukuoka, M. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann. Oncol., 2007, 18(2), 317-323.
[http://dx.doi.org/10.1093/annonc/mdl377] [PMID: 17079694]
[3]
Baselga, J.; Arteaga, C.L. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J. Clin. Oncol., 2005, 23(11), 2445-2459.
[http://dx.doi.org/10.1200/JCO.2005.11.890] [PMID: 15753456]
[4]
Yokoyama, T.; Tam, J.; Kuroda, S.; Scott, A.W.; Aaron, J.; Larson, T. EGFR-targeted hybrid plasmonic magnetic nanoparticles synergistically induce autophagy and apoptosis in non-small cell lung cancer cells. Plos One, 2011, 2011
[5]
Armour, A.A.; Watkins, C.L. The challenge of targeting EGFR: Experience with gefitinib in nonsmall cell lung cancer. Eur. Respir. Rev., 2010, 19(117), 186-196.
[http://dx.doi.org/10.1183/09059180.00005110] [PMID: 20956191]
[6]
Yang, C-H. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med., 2009, 361(10), 947-957.
[7]
Maemondo, M.; Inoue, A.; Kobayashi, K.; Sugawara, S.; Oizumi, S.; Isobe, H.; Gemma, A.; Harada, M.; Yoshizawa, H.; Kinoshita, I.; Fujita, Y.; Okinaga, S.; Hirano, H.; Yoshimori, K.; Harada, T.; Ogura, T.; Ando, M.; Miyazawa, H.; Tanaka, T.; Saijo, Y.; Hagiwara, K.; Morita, S.; Nukiwa, T. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med., 2010, 362(25), 2380-2388.
[http://dx.doi.org/10.1056/NEJMoa0909530] [PMID: 20573926]
[8]
Mitsudomi, T.; Morita, S.; Yatabe, Y.; Negoro, S.; Okamoto, I.; Tsurutani, J.; Seto, T.; Satouchi, M.; Tada, H.; Hirashima, T.; Asami, K.; Katakami, N.; Takada, M.; Yoshioka, H.; Shibata, K.; Kudoh, S.; Shimizu, E.; Saito, H.; Toyooka, S.; Nakagawa, K.; Fukuoka, M. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol., 2010, 11(2), 121-128.
[http://dx.doi.org/10.1016/S1470-2045(09)70364-X PMID: 20022809]
[9]
Pa, J. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat. Med., 2013, 1389-1400.
[10]
Mok, T.; Wu, Y.; Ahn, M.; Garassino, M.; Kim, H.; Ramalingam, S.; Shepherd, F.A.; He, Y.; Akamatsu, H.; Theelen, W.S.; Lee, C.K.; Sebastian, M.; Templeton, A.; Mann, H.; Marotti, M.; Ghiorghiu, S.; Papadimitrakopoulou, V.A. AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N. Engl. J. Med., 2017, 376(7), 629-640.
[11]
Sos, M.L.; Koker, M.; Weir, B.A.; Heynck, S.; Rabinovsky, R.; Zander, T.; Seeger, J.M.; Weiss, J.; Fischer, F.; Frommolt, P.; Michel, K.; Peifer, M.; Mermel, C.; Girard, L.; Peyton, M.; Gazdar, A.F.; Minna, J.D.; Garraway, L.A.; Kashkar, H.; Pao, W.; Meyerson, M.; Thomas, R.K. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res., 2009, 69(8), 3256-3261.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-4055 PMID: 19351834]
[12]
Vikhreva, P.N.; Shepelev, M.V.; Korobko, I.V. mTOR-dependent transcriptional repression of Pdcd4 tumor suppressor in lung cancer cells. Biochim. Biophys. Acta, 2014, 1839(1), 43-49.
[http://dx.doi.org/10.1016/j.bbagrm.2013.12.001] [PMID: 24334141]
[13]
Jiao, L.; Xu, J.; Sun, J.; Chen, Z.; Gong, Y.; Bi, L.; Lu, Y.; Yao, J.; Zhu, W.; Hou, A.; Feng, G.; Jia, Y.; Shen, W.; Li, Y.; Zhang, Z.; Chen, P.; Xu, L. Chinese herbal medicine combined with EGFR-TKI in EGFR Mutation-Positive Advanced Pulmonary Adenocarcinoma (CATLA): A multicenter, randomized, double-blind, placebo-controlled trial. Front. Pharmacol., 2019, 10, 732.
[http://dx.doi.org/10.3389/fphar.2019.00732] [PMID: 31333456]
[14]
Liu, J.; Pm, L.; Yuheng, Y.; Daqian, G.; Yinghua, L. Yongjian, Clinical study of oral liquid Jin Fu Kang for the treatment of primary non-small cell lung cancer. Tumor (Shanghai), 2001, 21(6), 463-465.
[15]
McCulloch, M.; See, C.; Shu, X.J.; Broffman, M.; Kramer, A.; Fan, W.Y.; Gao, J.; Lieb, W.; Shieh, K.; Colford, J.M., Jr Astragalus-based Chinese herbs and platinum-based chemotherapy for advanced non-small-cell lung cancer: Meta-analysis of randomized trials. J. Clin. Oncol., 2006, 24(3), 419-430.
[http://dx.doi.org/10.1200/JCO.2005.03.6392] [PMID: 16421421]
[16]
Lu, J.; Chen, J.; Kang, Y.; Wu, J.; Shi, H.; Fu, Y.; Jiao, L.; Dong, C.; Li, X.; Jin, Y.; Zhao, W.; Xu, L.; Zhao, X. Jinfukang induces cellular apoptosis through activation of Fas and DR4 in A549 cells. Oncol. Lett., 2018, 16(4), 4343-4352.
[http://dx.doi.org/10.3892/ol.2018.9149] [PMID: 30197670]
[17]
Zhang, L.; Jiang, Z.; Yang, J.; Li, Y.; Wang, Y.; Chai, X. Chemical material basis study of Xuefu Zhuyu decoction by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Yao Wu Shi Pin Fen Xi, 2015, 23(4), 811-820.
[http://dx.doi.org/10.1016/j.jfda.2015.06.004] [PMID: 28911499]
[18]
Yamamoto, C.; Basaki, Y.; Kawahara, A.; Nakashima, K.; Kage, M.; Izumi, H.; Kohno, K.; Uramoto, H.; Yasumoto, K.; Kuwano, M.; Ono, M. Loss of PTEN expression by blocking nuclear translocation of EGR1 in gefitinib-resistant lung cancer cells harboring epidermal growth factor receptor-activating mutations. Cancer Res., 2010, 70(21), 8715-8725.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-0043 PMID: 20959484]
[19]
Huang, D.; Chen, Y.; Chen, W.; Liu, Y.; Yao, F.; Xue, D.; Sun, L. Anti-inflammatory effects of the extract of Gnaphalium affine D. Don in vivo and in vitro. J. Ethnopharmacol., 2015, 176, 356-364.
[http://dx.doi.org/10.1016/j.jep.2015.11.010] [PMID: 26561928]
[20]
Jin, Y.; Xiao, Y.S.; Zhang, F.F.; Xue, X.Y.; Xu, Q.; Liang, X.M. Systematic screening and characterization of flavonoid glycosides in Carthamus tinctorius L. by liquid chromatography/UV diode-array detection/electrospray ionization tandem mass spectrometry. J. Pharm. Biomed. Anal., 2008, 46(3), 418-430.
[http://dx.doi.org/10.1016/j.jpba.2007.10.036] [PMID: 18082993]
[21]
Zheng, Y.F.; Qi, L.W.; Zhou, J.L.; Li, P. Structural characterization and identification of oleanane-type triterpene saponins in Glycyrrhiza uralensis Fischer by rapid-resolution liquid chromatography coupled with time-of-flight mass spectrometry. Rapid Commun. Mass Spectrom., 2010, 24(22), 3261-3270.
[http://dx.doi.org/10.1002/rcm.4768] [PMID: 20973000]
[22]
Simultaneous determination of seven compounds in Gandi capsules by UHPLC-MS/MS method. Yaowu Fenxi Zazhi, 2014, 4, 622-627.
[23]
Han, S-Y.; Zhao, W.; Sun, H.; Zhou, N.; Zhou, F.; An, G. Marsdenia tenacissima extract enhances gefitinib efficacy in non-small cell lung cancer xenografts. Phytomedicine, 2015, 22(5), 560-567.
[24]
Xiyuan, S.; Mei, J.; Zhongtai, Z.; Wei, Z.; Huiyu, X.; Junting, L. Effect of Jin fu kang oral liquid on apoptosis of human lung adenocarcina cell line PC-9R with gefitinib resistant. Liaoning J. Tradit. Chin. Med., 2014, 41 Corpus ID: 87566765
[25]
Jianli, S.; Jiaxiang, L. Effect of “Jinfukng Oral SoIution” on Express ion of apoptosis related genes of human lung adenocarcinomas cells transplanted in nude mice. Shanghai J. Ttrad. Chinese Med., 2007, 41, 69-71.
[26]
Garofalo, M.; Romano, G.; Di Leva, G.; Nuovo, G.; Jeon, Y-J.; Ngankeu, A.; Sun, J.; Lovat, F.; Alder, H.; Condorelli, G.; Engelman, J.A.; Ono, M.; Rho, J.K.; Cascione, L.; Volinia, S.; Nephew, K.P.; Croce, C.M. EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers. Nat. Med., 2011, 18(1), 74-82.
[http://dx.doi.org/10.1038/nm.2577] [PMID: 22157681]
[27]
Wang, S.I.; Puc, J.; Li, J.; Bruce, J.N.; Cairns, P.; Sidransky, D.; Parsons, R. Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res., 1997, 57(19), 4183-4186.
[PMID: 9331071]
[28]
Guldberg, P.; Straten, P.; Birck, A.; Ahrenkiel, V.; Kirkin, A.F.; Zeuthen, J. Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res., 1997, 27(17), 3660-3663.
[29]
Cairns, P.; Okami, K.; Halachmi, S.; Halachmi, N.; Esteller, M.; Herman, J.G.; Jen, J.; Isaacs, W.B.; Bova, G.S.; Sidransky, D. Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res., 1997, 57(22), 4997-5000.
[PMID: 9371490]
[30]
Rhei, E.; Kang, L.; Bogomolniy, F.; Federici, M.G.; Borgen, P.I.; Boyd, J. Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas. Cancer Res., 1997, 57(17), 3657-3659.
[31]
Kohno, T.; Takahashi, M.; Manda, R.; Yokota, J. Inactivation of the PTEN/MMAC1/TEP1 gene in human lung cancers. Genes Chromosomes Cancer, 1998, 22(2), 152-156.
[http://dx.doi.org/10.1002/(SICI)1098-2264(199806)22:2<152:AID-GCC10>3.0.CO;2-S] [PMID: 9598803]
[32]
Tashiro, H.; Blazes, M.S.; Wu, R.; Cho, K.R.; Bose, S.; Wang, S.I.; Li, J.; Parsons, R.; Ellenson, L.H. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res., 1997, 57(18), 3935-3940.
[PMID: 9307275]
[33]
Maehama, T.; Dixon, J.E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem., 1998, 273(22), 13375-13378.
[http://dx.doi.org/10.1074/jbc.273.22.13375] [PMID: 9593664]
[34]
Auger, K.R.; Serunian, L.A.; Soltoff, S.P.; Libby, P. Cantley. L.C. PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells. Cell, 1989, 57(1), 167-175.
[35]
Myers, M.P.; Pass, I.; Batty, I.H.; Kaay, J.V.; Stolarov, J.P.; Hemmings, B.A.; Wigler, M.H.; Downes, C.P.; Tonks, N.K. The lipid phosphatase activity of PTEN is critical for its tumor suppressor function. Proc. Natl. Acad. Sci. USA, 1998, 95(23), 13513-13518.
[36]
Haas-Kogan, D.; Shalev, N.; Wong, M.; Mills, G.; Yount, G.; Stokoe, D. Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC. Curr. Biol., 1998, 8(21), 1195-1198.
[http://dx.doi.org/10.1016/S0960-9822(07)00493-9] [PMID: 9799739]
[37]
Dudek, H.; Datta, S.R.; Franke, T.F.; Birnbaum, M.J.; Yao, R.; Cooper, G.M.; Segal, R.A.; Kaplan, D.R.; Greenberg, M.E. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science, 1997, 275(5300), 661-665.
[http://dx.doi.org/10.1126/science.275.5300.661] [PMID: 9005851]
[38]
Kalinichenko, S.V.; Kopantzev, E.P.; Korobko, E.V.; Palgova, I.V.; Zavalishina, L.E.; Bateva, M.V.; Petrov, A.N.; Frank, G.A.; Sverdlov, E.D.; Korobko, I.V. Pdcd4 protein and mRNA level alterations do not correlate in human lung tumors. Lung Cancer, 2008, 62(2), 173-180.
[http://dx.doi.org/10.1016/j.lungcan.2008.03.022] [PMID: 18457901]
[39]
Schmid, T.; Jansen, A.P.; Baker, A.R.; Hegamyer, G.; Hagan, J.P.; Colburn, N.H. Translation inhibitor Pdcd4 is targeted for degradation during tumor promotion. Cancer Res., 2008, 68(5), 1254-1260.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-1719 PMID: 18296647]
[40]
Pu, Y.; Zhang, T.; Wang, J.; Mao, Z.; Duan, B.; Long, Y.; Xue, F.; Liu, D.; Liu, S.; Gao, Z. Luteolin exerts an anticancer effect on gastric cancer cells through multiple signaling pathways and regulating miRNAs. J. Cancer, 2018, 9(20), 3669-3675.
[http://dx.doi.org/10.7150/jca.27183] [PMID: 30405835]
[41]
Xavier, C.P.R.; Lima, C.F.; Preto, A.; Seruca, R.; Fernandes-Ferreira, M.; Pereira-Wilson, C. Luteolin, quercetin and ursolic acid are potent inhibitors of proliferation and inducers of apoptosis in both KRAS and BRAF mutated human colorectal cancer cells. Cancer Lett., 2009, 281(2), 162-170.
[http://dx.doi.org/10.1016/j.canlet.2009.02.041] [PMID: 19344998]
[42]
Liu, L-Z.; Fang, J.; Zhou, Q.; Hu, X.; Shi, X.; Jiang, B-H. Apigenin inhibits expression of vascular endothelial growth factor and angiogenesis in human lung cancer cells: Implication of chemoprevention of lung cancer. Mol. Pharmacol., 2005, 68(3), 635-643.
[http://dx.doi.org/10.1124/mol.105.011254] [PMID: 15947208]
[43]
Fang, J.; Xia, C.; Cao, Z.; Zheng, J.Z.; Reed, E.; Jiang, B-H. Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways. FASEB J., 2005, 19(3), 342-353.
[http://dx.doi.org/10.1096/fj.04-2175com] [PMID: 15746177]
[44]
Weldon, C.B.; McKee, A.; Collins-Burow, B.M.; Melnik, L.I.; Scandurro, A.B.; McLachlan, J.A.; Burow, M.E.; Beckman, B.S. PKC-mediated survival signaling in breast carcinoma cells: a role for MEK1-AP1 signaling. Int. J. Oncol., 2005, 26(3), 763-768.
[http://dx.doi.org/10.3892/ijo.26.3.763] [PMID: 15703835]
[45]
Sabarinathan, D.; Vanisree, A.J. Plausible role of naringenin against cerebrally implanted C6 glioma cells in rats. Mol. Cell. Biochem., 2013, 375(1-2), 171-178.
[PMID: 23263903]
[46]
Li, Q.; Huai, L.; Zhang, C.; Wang, C.; Jia, Y.; Chen, Y.; Yu, P.; Wang, H.; Rao, Q.; Wang, M.; Wang, J. Icaritin induces AML cell apoptosis via the MAPK/ERK and PI3K/AKT signal pathways. Int. J. Hematol., 2013, 97(5), 617-623.
[http://dx.doi.org/10.1007/s12185-013-1317-9] [PMID: 23550021]
[47]
Wu, J.; Zuo, F.; Du, J.; Wong, P.F.; Qin, H.; Xu, J. Icariside II induces apoptosis via inhibition of the EGFR pathways in A431 human epidermoid carcinoma cells. Mol. Med. Rep., 2013, 8(2), 597-602.
[http://dx.doi.org/10.3892/mmr.2013.1557] [PMID: 23807305]
[48]
Chen, M.; Du, Y.; Qui, M.; Wang, M.; Chen, K.; Huang, Z.; Jiang, M.; Xiong, F.; Chen, J.; Zhou, J.; Jiang, F.; Yin, L.; Tang, Y.; Ye, L.; Zhan, Z.; Duan, J.A.; Fu, H.A.; Zhang, X. Ophiopogonin B-induced autophagy in non-small cell lung cancer cells via inhibition of the PI3K/Akt signaling pathway. Oncol. Rep., 2013, 29(2), 430-436.
[http://dx.doi.org/10.3892/or.2012.2131] [PMID: 23151908]

Rights & Permissions Print Cite
Article Metrics
28
1
© 2024 Bentham Science Publishers | Privacy Policy