Effect of Hsp90 Inhibitor Ganetespib Combined with Pemetrexed on Lung Adenocarcinoma Cells

Shengqiang YANG; Ping WANG

doi:10.12259/j.issn.2095-610X.S20240705

Volume 45 Issue 7

Jul. 2024

Turn off MathJax

Article Contents

Article Navigation > Journal of Kunming Medical University > 2024 > 45(7): 30-41

Shengqiang YANG, Ping WANG. Effect of Hsp90 Inhibitor Ganetespib Combined with Pemetrexed on Lung Adenocarcinoma Cells[J]. Journal of Kunming Medical University, 2024, 45(7): 30-41. doi: 10.12259/j.issn.2095-610X.S20240705

Citation:

Shengqiang YANG, Ping WANG. Effect of Hsp90 Inhibitor Ganetespib Combined with Pemetrexed on Lung Adenocarcinoma Cells[J]. Journal of Kunming Medical University, 2024, 45(7): 30-41. doi: 10.12259/j.issn.2095-610X.S20240705

Citation:

PDF( 1868 KB)

Effect of Hsp90 Inhibitor Ganetespib Combined with Pemetrexed on Lung Adenocarcinoma Cells

doi: 10.12259/j.issn.2095-610X.S20240705

Shengqiang YANG,
Ping WANG^,

Dept. of Thoracic Surgery，The 2nd Affiliated Hospital of Kunming Medical University，Kunming Yunnan 650032，China

Received Date: 2024-03-12
Available Online: 2024-06-15
Publish Date: 2024-07-25

Abstract

Abstract

Objective To investigate the effects of Ganetespib and Pemetrexed on the proliferation, apoptosis and related signaling pathways of human lung adenocarcinoma cells in vitro. Methods Human lung adenocarcinoma cells HCC827, H1975, and A549 were divided into groups （Ganetespib group, pemetrexed group, combined treatment group）, and a control group （DMSO 0.2%） was set up. After culturing for 48 hours, the Cell Titer-Glo （CTG） method was used to detect the inhibitory effects of cell proliferation in vitro, and Western blot was used to detect the expression levels of Akt, p-Akt, and Bcl-2 proteins in cells. The apoptosis experiment was used to detect the apoptosis rate, and RNA-seq was used to detect the effects of the two drugs on the transcription level of the HCC827 cell line. Results The inhibitory effects of cell proliferation were as follows: Ganetespib > pemetrexed （P < 0.001）, and the inhibitory effect was enhanced when the two drugs were combined （P < 0.0001）; the apoptosis rate was as follows: Ganetespib > pemetrexed （P < 0.05）, and the apoptosis rate of HCC827 cells increased when the two drugs were combined; the phosphorylation level of Akt protein was lower in the Ganetespib group （P < 0.05）, and the phosphorylation level of Akt protein was higher in the pemetrexed group （P < 0.05）, and the results of the combined treatment group were similar to those of the Ganetespib group, and Bcl-2 protein was only downregulated in A549 cells （P < 0.01）; the two drugs had an effect on the gene transcription level of the HCC827 cell line, with 102 upregulated differentially expressed genes and 27 downregulated genes in the Ganetespib group, 53 upregulated differentially expressed genes and 8 downregulated genes in the pemetrexed group. Conclusion The combination of Ganetespib and pemetrexed can significantly inhibit the proliferation of lung adenocarcinoma cells HCC827, H1975, and A549, induce cell apoptosis. The molecular mechanism may be through the inhibition of lung adenocarcinoma cell proliferation by protein phosphorylation in the PI3K/AKT signaling pathway. The transcriptome of HCC827 cells was affected by the combination therapy. The combined treatment can enhance the inhibition of lung adenocarcinoma cell proliferation to some extent, and the specific mechanism needs further research.
- Lung adenocarcinoma,
- Ganetespib,
- Pemetrexed

FullText(HTML)

References(36)

References

[1]	Lee E,Kazerooni E A. Lung cancer screening[J]. Seminars in Respiratory and Critical Care Medicine,2022,43(6):839-850. doi: 10.1055/s-0042-1757885
[2]	Schabath M B, Cote M L. Cancer progress and priorities: Lung cancer [J]. Cancer Epidemiology, Biomarkers & Prevention, 2019, 28（10）: 1563-1579. Schabath M B,Cote M L. Cancer progress and priorities: Lung cancer [J]. Cancer Epidemiology,Biomarkers & Prevention,2019,28(10): 1563-1579.
[3]	Sung H,Ferlay J,Siegel R L,et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer Journal for Clinicians,2021,71(3):209-249. doi: 10.3322/caac.21660
[4]	Goss P E,Strasser-weippl K,Lee-bychkovsky B L,et al. Challenges to effective cancer control in China,India,and Russia[J]. Lancet Oncology,2014,15(5):489-538. doi: 10.1016/S1470-2045(14)70029-4
[5]	Ruiz-cordero R,Devine W P. Targeted therapy and checkpoint immunotherapy in lung cancer[J]. Surgical Pathology Clinics,2020,13(1):17-33. doi: 10.1016/j.path.2019.11.002
[6]	Chaft J E,Shyr Y,Sepesi B,et al. Preoperative and postoperative systemic therapy for operable non-small-cell lung cancer[J]. Journal of Clinical Oncology,2022,40(6):546-555. doi: 10.1200/JCO.21.01589
[7]	Yousefi M,Bahrami T,Salmaninejad A,et al. Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic options[J]. Cellular Oncology (Dordrecht),2017,40(5):419-441. doi: 10.1007/s13402-017-0345-5
[8]	Yousefi M E,Cavalu S,Hasan A M,et al. Role of ganetespib,An HSP90 inhibitor,in cancer therapy: From molecular mechanisms to clinical practice[J]. International Journal of Molecular Sciences,2023,24(5):.5014 doi: 10.3390/ijms24055014
[9]	Birbo B,Madu E E,Madu C O,et al. Role of HSP90 in cancer[J]. International Journal of Molecular Sciences,2021,22(19):.10317 doi: 10.3390/ijms221910317
[10]	Stivarou T,Patsavoudi E. Extracellular molecules involved in cancer cell invasion[J]. Cancers,2015,7(1):238-265. doi: 10.3390/cancers7010238
[11]	Proia D A,Foley K P,Korbut T,et al. Multifaceted intervention by the Hsp90 inhibitor ganetespib (STA-9090) in cancer cells with activated JAK/STAT signaling[J]. PloS One,2011,6(4):e18552. doi: 10.1371/journal.pone.0018552
[12]	Xiang L,Gilkes D M,Chaturvesi P,et al. Ganetespib blocks HIF-1 activity and inhibits tumor growth,vascularization,stem cell maintenance,invasion,and metastasis in orthotopic mouse models of triple-negative breast cancer[J]. Journal of Molecular Medicine (Berlin,Germany),2014,92(2):151-164. doi: 10.1007/s00109-013-1102-5
[13]	Gadgeel S,Rodriguez-abreu D,Speranza G,et al. Updated analysis from KEYNOTE-189: Pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer[J]. Journal of Clinical Oncology,2020,38(14):1505-1517. doi: 10.1200/JCO.19.03136
[14]	Zhang J,Song C,Tian Y,et al. Single-cell RNA sequencing in lung cancer: Revealing phenotype shaping of stromal cells in the microenvironment[J]. Frontiers in Iimmunology,2021,12:802080.
[15]	Hirsch F R,Scagliotti G V,Mulshine J L,et al. Lung cancer: current therapies and new targeted treatments[J]. Lancet,2017,389(10066):299-311. doi: 10.1016/S0140-6736(16)30958-8
[16]	Park S,Keam B,Kim S H,et al. Pemetrexed singlet versus nonpemetrexed-based platinum doublet as second-line chemotherapy after first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor failure in non-small cell lung cancer patients with EGFR mutations[J]. Cancer Research and Treatment,2015,47(4):630-637. doi: 10.4143/crt.2014.244
[17]	Jones G S,Baldwin D R. Recent advances in the management of lung cancer[J]. Clinical Medicine (London,England),2018,18(Suppl 2):s41-s46.
[18]	Yoshimura N,Okishio K,Mitsuoka S,et al. Prospective assessment of continuation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of pemetrexed[J]. Journal of Thoracic Oncology,2013,8(1):96-101. doi: 10.1097/JTO.0b013e3182762bfb
[19]	Fuld A D,Dragnev K H,Rigas J R. Pemetrexed in advanced non-small-cell lung cancer[J]. Expert Opinion on Pharmacotherapy,2010,11(8):1387-1402. doi: 10.1517/14656566.2010.482560
[20]	Wu S G,Yang C H,Yu C J,et al. Good response to pemetrexed in patients of lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations[J]. Lung Cancer,2011,72(3):333-339. doi: 10.1016/j.lungcan.2010.10.012
[21]	Cui J,Zhang Y,Su D,et al. Efficacy of combined icotinib and pemetrexed in EGFR mutant lung adenocarcinoma cell line xenografts[J]. Thoracic Cancer,2018,9(9):1156-1165. doi: 10.1111/1759-7714.12818
[22]	Feng X,Zhang Y,Li T,et al. Sequentially administrated of pemetrexed with icotinib/erlotinib in lung adenocarcinoma cell lines in vitro[J]. Oncotarget,2017,8(69):114292-114299. doi: 10.18632/oncotarget.23224
[23]	Noronha V,Patil V M,Joshi A,et al. Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer[J]. Journal of Clinical Oncology,2020,38(2):124-136. doi: 10.1200/JCO.19.01154
[24]	Taipale M,Jarosz D F,Lindquist S. HSP90 at the hub of protein homeostasis: Emerging mechanistic insights[J]. Nature Reviews Molecular Cell Biology,2010,11(7):515-528. doi: 10.1038/nrm2918
[25]	Shimamura T,Li D,JI H,et al. Hsp90 inhibition suppresses mutant EGFR-T790M signaling and overcomes kinase inhibitor resistance[J]. Cancer Research,2008,68(14):5827-5838. doi: 10.1158/0008-5472.CAN-07-5428
[26]	Acquaviva J,Smith D L,Sang J,et al. Targeting KRAS-mutant non-small cell lung cancer with the Hsp90 inhibitor ganetespib[J]. Molecular Cancer Therapeutics,2012,11(12):2633-2643. doi: 10.1158/1535-7163.MCT-12-0615
[27]	Sequist L V,Gettinger S,Senzer N N,et al. Activity of IPI-504,a novel heat-shock protein 90 inhibitor,in patients with molecularly defined non-small-cell lung cancer[J]. Journal of Clinical Oncology,2010,28(33):4953-4960. doi: 10.1200/JCO.2010.30.8338
[28]	Neckers L,Workman P. Hsp90 molecular chaperone inhibitors: Are we there yet?[J]. Clinical Cancer Research,2012,18(1):64-76. doi: 10.1158/1078-0432.CCR-11-1000
[29]	Proia D A,Sang J,HE S,et al. Synergistic activity of the Hsp90 inhibitor ganetespib with taxanes in non-small cell lung cancer models[J]. Investigational New Drugs,2012,30(6):2201-2209. doi: 10.1007/s10637-011-9790-6
[30]	Smith D L,Acquaviva J,Sequeira M,et al. The HSP90 inhibitor ganetespib potentiates the antitumor activity of EGFR tyrosine kinase inhibition in mutant and wild-type non-small cell lung cancer[J]. Targeted Oncology,2015,10(2):235-245. doi: 10.1007/s11523-014-0329-6
[31]	Fennell D A,Danson S,Woll P J,et al. Ganetespib in combination with pemetrexed-platinum chemotherapy in patients with pleural mesothelioma (MESO-02): A phase Ib trial[J]. Clinical Cancer Research,2020,26(18):4748-4755. doi: 10.1158/1078-0432.CCR-20-1306
[32]	Stecklein S R,Kumaraswamy E,Behbod F,et al. BRCA1 and HSP90 cooperate in homologous and non-homologous DNA double-strand-break repair and G2/M checkpoint activation[J]. Proceedings of the National Academy of Sciences of the United States of America,2012,109(34):13650-13655.
[33]	Abu Lila A S,Kato C,Fukshima M,et al. Downregulation of thymidylate synthase by RNAi molecules enhances the antitumor effect of pemetrexed in an orthotopic malignant mesothelioma xenograft mouse model[J]. International Journal of Oncology,2016,48(4):1399-1407. doi: 10.3892/ijo.2016.3367
[34]	Zucali P A,Giovannetti E,Destro A,et al. Thymidylate synthase and excision repair cross-complementing group-1 as predictors of responsiveness in mesothelioma patients treated with pemetrexed/carboplatin[J]. Clinical Cancer Research,2011,17(8):2581-2590. doi: 10.1158/1078-0432.CCR-10-2873
[35]	Deng Z,Qin Y,Liu Y,et al. Role of antiangiogenic agents combined with EGFR tyrosine kinase inhibitors in treatment-naive lung cancer: A meta-analysis[J]. Clinical Lung Cancer,2021,22(1):e70-e83. doi: 10.1016/j.cllc.2020.08.005
[36]	Xue J,Li B,Wang Y,et al. Efficacy and safety of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor combination therapy as first-line treatment for patients with advanced EGFR-mutated,non-small cell lung cancer: A systematic review and bayesian network meta-analysis[J]. Cancers,2022,14(19):4894. doi: 10.3390/cancers14194894

Relative Articles(20)

Relative Articles

[1]	Wangxun SHEN, Yinyu YANG, Canwei LI, Jinrong YANG, Sijing WU, Huajun ZHAO, Xiaoyu TUO. Expression and Clinical Significance of ROR1 in Different Histologic Types of Invasive Lung Adenocarcinoma. Journal of Kunming Medical University, 2024, 45(5): 60-65. doi: 10.12259/j.issn.2095-610X.S20240509
[2]	Hongxiu YANG, Zhongshan ZHU. Effect of HPRT1 Gene Expression on Overall Survival of Patients with Lung Adenocarcinoma. Journal of Kunming Medical University, 2024, 45(8): 17-23. doi: 10.12259/j.issn.2095-610X.S20240803
[3]	Fei SONG, Jiayin CHE, Ming HUANG, Dan XU, Hongyang LI, Dingkun LI, Yingying XIANG. The Role of Radioactive Iodine-125 Particles in EMT and Clinical Treatment of Lung Adenocarcinoma. Journal of Kunming Medical University, 2023, 44(1): 140-143. doi: 10.12259/j.issn.2095-610X.S20230101
[4]	Shiqi MA, Yi DING, Min LI, Mengci WANG, Siyu ZHANG, Shumei FENG. LINC00341 Inhibits the Proliferation of Lung Adenocarcinoma Cells Through the MAPK Pathway. Journal of Kunming Medical University, 2023, 44(4): 1-8. doi: 10.12259/j.issn.2095-610X.S20230403
[5]	Bangqing LIU, Jianfeng LI, Xiaohui LIU, Jinnan ZHANG, Jinping LIANG. MiR-196b Promotes Proliferation and Migration of Lung Adenocarcinoma by Targeting ERG. Journal of Kunming Medical University, 2023, 44(10): 83-91. doi: 10.12259/j.issn.2095-610X.S20231023
[6]	Huajun ZHAO, Guoqing PAN, Ying TANG, Zhiyuan WANG, Xiaowei ZHAO, Xiaoyu TUO. Expressions of ROR1 in Lung Adenocarcinoma and Its Relationship with Spread Through Air Apace. Journal of Kunming Medical University, 2022, 43(11): 22-29. doi: 10.12259/j.issn.2095-610X.S20221128
[7]	Zhongshan ZHU, Zhou YANG, Chengchuan JIANG, Xiaobing LI, Dou REN, Cheng HUANG, Weiwei ZHANG, Xiangjun LI, Shunli ZHAO. An Analysis of PLA2G1B Expression and Prognosis in Patients with Lung Adenocarcinoma. Journal of Kunming Medical University, 2022, 43(9): 70-76. doi: 10.12259/j.issn.2095-610X.S20220912
[8]	Maofang WU, Yongchun ZHOU, Jingjing CAI, Xin MO, Yinwei LI, Jiahui MAO. EGFR Gene Mutation State and Its Clinical Significance in Multi-nodular Lung Adenocarcinoma in Yunnan Province. Journal of Kunming Medical University, 2022, 43(2): 60-66. doi: 10.12259/j.issn.2095-610X.S20220215
[9]	Ying-xia WANG, Qin HE, Guo-fang WANG, Xuan ZHANG. Expression and Significance of microRNA-21 and EGFR in Non-small Cell Lung Cancer. Journal of Kunming Medical University, 2021, 42(8): 101-105. doi: 10.12259/j.issn.2095-610X.S20210818
[10]	Hong-min DUAN, Nan CHEN, Yong-yan YANG, Yun-xia LI, Jin-xiang FENG, Hang LI, Xiu-wen HUANG, Dong-jin LV, Ming ZHANG, Yu-tao ZHAO. Effects and Mechanism of Anlotinib on Radiosensitivity of Non-small Cell Lung Cancer Cell Lines A549. Journal of Kunming Medical University, 2021, 42(8): 40-46. doi: 10.12259/j.issn.2095-610X.S20210808
[11]	Yan-fen MA, Jian HU, Ning ZHANG, Qian WU, Xiao-qin WANG. Changes and Abnormal Patterns of Coagulation Indicators in Patients with Lung Adenocarcinoma and Tuberculosis Pleural Effusion. Journal of Kunming Medical University, 2021, 42(10): 145-150. doi: 10.12259/j.issn.2095-610X.S20211021
[12]	Ma Guo Yu , Xiong Qing , Jiang Guo Qing , Yang Jia Tian , Mu Yun Zhen . . Journal of Kunming Medical University, 2020, 41(07): 30-37.
[13]	Wu Qi Yan , Bian Ge Yuan , Cheng Hui Jun, Li Jiao Xia , Wang Shu Ting , Huang Zhao Lue . . Journal of Kunming Medical University, 2020, 41(09): 32-37.
[14]	Zhu Zhong Shan , Yan Wen Hui , Li Xiao Bing , Yang Zhou , Bai Peng . Driver Genes Mutation and Survival Analysis in 200 Patients with Pulmonary Adenocarcinoma Brain Metastasis. Journal of Kunming Medical University, 2018, 39(08): 47-50.
[15]	Wang Hua . . Journal of Kunming Medical University,
[16]	Ren Hong Xuan . . Journal of Kunming Medical University,
[17]	. Expression of GDNF,BDNF,NT3 and NT4 in Human Lung Adenocarcinoma Cell Lines A549. Journal of Kunming Medical University,
[18]	. Expression of GDNF and Changes of Cell Viability of Lung Adenocarcinoma Cell Lines A549. Journal of Kunming Medical University,
[19]	. The Comparison of Cell Viability between Xuanwei Lung Adenocarcinoma Cell Lines xwlc-05 and Cell Lines A549 in Vitro. Journal of Kunming Medical University,
[20]	. Expression of study of Nestin in Lung Adenocarcinoma Cell Line A549. Journal of Kunming Medical University,