Issue
TW37 enhances the pro-apoptosis and anti-migration ability of gefitinib in Non-Small Cell Lung Cancer
Corresponding Author(s) : Jixian Liu
Cellular and Molecular Biology,
Vol. 64 No. 4: Issue 4
Abstract
B cell leukemia-2 (Bcl-2) plays important roles in the development of tumor and drug resistance. The growth of tumor cells can be inhibited by downregulating the abnormal expression of Bcl-2 protein. TW37, an effective inhibitor of Bcl-2 protein, has now been widely studied in many tumors. In our study, it was found that TW37 exerted a significant effect on the proliferation, apoptosis and migration of Non-Small Cell Lung Cancer cells. Bcl-2 is also a key downstream factor of many signaling pathways such as Epidermal Growth Factor Receptor (EGFR). TW37 enhanced the inhibition of tumorigenesis by gefitinib, an EGFR-Tyrosine Kinase Inhibitor drug. Moreover, TW37 can promote apoptosis ability by inhibiting the phosphorylation level of EGFR protein in H1975 cells. Overall, TW37 enhances the pro-apoptosis and anti-migration ability of gefitinib in Non-Small Cell Lung Cancer.
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- Yang L, Parkin DM, Li LD, Chen YD and Bray F. Estimation and projection of the national profile of cancer mortality in China: 1991-2005. Br J Cancer 2004; 90: 2157-66.
- Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H, et al., Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol 2013; 24: 54-9.
- Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al., 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: 121-8.
- Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al., Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31: 3327-34.
- Pao W, Wang TY, Riely GJ, Miller VA, Pan Q, Ladanyi M, et al., KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2005; 2: e17.
- Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, et al., EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005; 352: 786-92.
- Inukai M, Toyooka S, Ito S, Asano H, Ichihara S, Soh J, et al., Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer Res 2006; 66: 7854-8.
- Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, et al., An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005; 435: 677-81.
- Lee HW, Choi YW, Han JH, Kim JH, Jung JH, Jeong SH, et al., Expression of excision repair cross-complementation group 1 protein predicts poor outcome in advanced non-small cell lung cancer patients treated with platinum-based doublet chemotherapy. Lung Cancer 2009; 65: 377-82.
- Koty PP, Zhang H, Franklin WA, Yousem SA, Landreneau R and Levitt ML. In vivo expression of p53 and Bcl-2 and their role in programmed cell death in premalignant and malignant lung lesions. Lung Cancer 2002; 35: 155-63.
- Meng Y, Li Y, Li J, Li H, Fu J, Liu Y, et al., (-)Gossypol and its combination with imatinib induce apoptosis in human chronic myeloid leukemic cells. Leuk Lymphoma 2007; 48: 2204-12.
- Mohammad RM, Wang S, Aboukameel A, Chen B, Wu X, Chen J, et al., Preclinical studies of a nonpeptidic small-molecule inhibitor of Bcl-2 and Bcl-X(L) [(-)-gossypol] against diffuse large cell lymphoma. Mol Cancer Ther 2005; 4: 13-21.
- Mohammad RM, Goustin AS, Aboukameel A, Chen B, Banerjee S, Wang G, et al., Preclinical studies of TW-37, a new nonpeptidic small-molecule inhibitor of Bcl-2, in diffuse large cell lymphoma xenograft model reveal drug action on both Bcl-2 and Mcl-1. Clin Cancer Res 2007; 13: 2226-35.
- Wang Z, Azmi AS, Ahmad A, Banerjee S, Wang S, Sarkar FH, et al., TW-37, a small-molecule inhibitor of Bcl-2, inhibits cell growth and induces apoptosis in pancreatic cancer: involvement of Notch-1 signaling pathway. Cancer Res 2009; 69: 2757-65.
- Ashimori N, Zeitlin BD, Zhang Z, Warner K, Turkienicz IM, Spalding AC, et al., TW-37, a small-molecule inhibitor of Bcl-2, mediates S-phase cell cycle arrest and suppresses head and neck tumor angiogenesis. Mol Cancer Ther 2009; 8: 893-903.
- Zeitlin BD, Joo E, Dong Z, Warner K, Wang G, Nikolovska-Coleska Z, et al., Antiangiogenic effect of TW37, a small-molecule inhibitor of Bcl-2. Cancer Res 2006; 66: 8698-706.
- Andoniou CE, Andrews DM, Manzur M, Ricciardi-Castagnoli P and Degli-Esposti MA. A novel checkpoint in the Bcl-2-regulated apoptotic pathway revealed by murine cytomegalovirus infection of dendritic cells. J Cell Biol 2004; 166: 827-37.
- Hu ZY, Zhu XF, Zhong ZD, Sun J, Wang J, Yang D, et al., ApoG2, a novel inhibitor of antiapoptotic Bcl-2 family proteins, induces apoptosis and suppresses tumor growth in nasopharyngeal carcinoma xenografts. Int J Cancer 2008; 123: 2418-29.
- Vanasse GJ, Winn RK, Rodov S, Zieske AW, Li JT, Tupper JC, et al., Bcl-2 overexpression leads to increases in suppressor of cytokine signaling-3 expression in B cells and de novo follicular lymphoma. Mol Cancer Res 2004; 2: 620-31.
- Del Vecchio S, Zannetti A, Aloj L, Caraco C, Ciarmiello A and Salvatore M. Inhibition of early 99mTc-MIBI uptake by Bcl-2 anti-apoptotic protein overexpression in untreated breast carcinoma. Eur J Nucl Med Mol Imaging 2003; 30: 879-87.
- Badaracco G, Venuti A, Bartolazzi A, Morello R, Marzetti F and Marcante ML. Overexpression of p53 and bcl-2 proteins and the presence of HPV infection are independent events in head and neck cancer. J Oral Pathol Med 2000; 29: 173-9.
- Grace VM, Shalini JV, lekha TT, Devaraj SN and Devaraj H. Co-overexpression of p53 and bcl-2 proteins in HPV-induced squamous cell carcinoma of the uterine cervix. Gynecol Oncol 2003; 91: 51-8.
- Cervero C, Escribano L, San Miguel JF, Diaz-Agustin B, Bravo P, Villarrubia J, et al., Expression of Bcl-2 by human bone marrow mast cells and its overexpression in mast cell leukemia. Am J Hematol 1999; 60: 191-5.
- Wang H, Zhang Z, Wei X and Dai R. Small-molecule inhibitor of Bcl-2 (TW-37) suppresses growth and enhances cisplatin-induced apoptosis in ovarian cancer cells. J Ovarian Res 2015; 8: 3.
- Shi X, Dou Y, Zhou K, Huo J, Yang T, Qin T, et al., Targeting the Bcl-2 family and P-glycoprotein reverses paclitaxel resistance in human esophageal carcinoma cell line. Biomed Pharmacother 2017; 90: 897-905.
- Li G, Liu L, Shan C, Cheng Q, Budhraja A, Zhou T, et al., RhoA/ROCK/PTEN signaling is involved in AT-101-mediated apoptosis in human leukemia cells in vitro and in vivo. Cell Death Dis 2014; 5: e998.
- Sadahira K, Sagawa M, Nakazato T, Uchida H, Ikeda Y, Okamoto S, et al., Gossypol induces apoptosis in multiple myeloma cells by inhibition of interleukin-6 signaling and Bcl-2/Mcl-1 pathway. Int J Oncol 2014; 45: 2278-86.
- Balakrishnan K, Wierda WG, Keating MJ and Gandhi V. Gossypol, a BH3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells. Blood 2008; 112: 1971-80.
- Sun J, Li ZM, Hu ZY, Lin XB, Zhou NN, Xian LJ, et al., ApoG2 inhibits antiapoptotic Bcl-2 family proteins and induces mitochondria-dependent apoptosis in human lymphoma U937 cells. Anticancer Drugs 2008; 19: 967-74.
- Voss V, Senft C, Lang V, Ronellenfitsch MW, Steinbach JP, Seifert V, et al., The pan-Bcl-2 inhibitor (-)-gossypol triggers autophagic cell death in malignant glioma. Mol Cancer Res 2010; 8: 1002-16.
- He JH, Liao XL, Wang W, Li DD, Chen WD, Deng R, et al., Apogossypolone, a small-molecule inhibitor of Bcl-2, induces radiosensitization of nasopharyngeal carcinoma cells by stimulating autophagy. Int J Oncol 2014; 45: 1099-108.
- Cheng P, Ni Z, Dai X, Wang B, Ding W, Rae Smith A, et al., The novel BH-3 mimetic apogossypolone induces Beclin-1- and ROS-mediated autophagy in human hepatocellular carcinoma cells. Cell Death Dis 2013; 4: e489.
References
Yang L, Parkin DM, Li LD, Chen YD and Bray F. Estimation and projection of the national profile of cancer mortality in China: 1991-2005. Br J Cancer 2004; 90: 2157-66.
Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H, et al., Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol 2013; 24: 54-9.
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al., 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: 121-8.
Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al., Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31: 3327-34.
Pao W, Wang TY, Riely GJ, Miller VA, Pan Q, Ladanyi M, et al., KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2005; 2: e17.
Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, et al., EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005; 352: 786-92.
Inukai M, Toyooka S, Ito S, Asano H, Ichihara S, Soh J, et al., Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer Res 2006; 66: 7854-8.
Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, et al., An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005; 435: 677-81.
Lee HW, Choi YW, Han JH, Kim JH, Jung JH, Jeong SH, et al., Expression of excision repair cross-complementation group 1 protein predicts poor outcome in advanced non-small cell lung cancer patients treated with platinum-based doublet chemotherapy. Lung Cancer 2009; 65: 377-82.
Koty PP, Zhang H, Franklin WA, Yousem SA, Landreneau R and Levitt ML. In vivo expression of p53 and Bcl-2 and their role in programmed cell death in premalignant and malignant lung lesions. Lung Cancer 2002; 35: 155-63.
Meng Y, Li Y, Li J, Li H, Fu J, Liu Y, et al., (-)Gossypol and its combination with imatinib induce apoptosis in human chronic myeloid leukemic cells. Leuk Lymphoma 2007; 48: 2204-12.
Mohammad RM, Wang S, Aboukameel A, Chen B, Wu X, Chen J, et al., Preclinical studies of a nonpeptidic small-molecule inhibitor of Bcl-2 and Bcl-X(L) [(-)-gossypol] against diffuse large cell lymphoma. Mol Cancer Ther 2005; 4: 13-21.
Mohammad RM, Goustin AS, Aboukameel A, Chen B, Banerjee S, Wang G, et al., Preclinical studies of TW-37, a new nonpeptidic small-molecule inhibitor of Bcl-2, in diffuse large cell lymphoma xenograft model reveal drug action on both Bcl-2 and Mcl-1. Clin Cancer Res 2007; 13: 2226-35.
Wang Z, Azmi AS, Ahmad A, Banerjee S, Wang S, Sarkar FH, et al., TW-37, a small-molecule inhibitor of Bcl-2, inhibits cell growth and induces apoptosis in pancreatic cancer: involvement of Notch-1 signaling pathway. Cancer Res 2009; 69: 2757-65.
Ashimori N, Zeitlin BD, Zhang Z, Warner K, Turkienicz IM, Spalding AC, et al., TW-37, a small-molecule inhibitor of Bcl-2, mediates S-phase cell cycle arrest and suppresses head and neck tumor angiogenesis. Mol Cancer Ther 2009; 8: 893-903.
Zeitlin BD, Joo E, Dong Z, Warner K, Wang G, Nikolovska-Coleska Z, et al., Antiangiogenic effect of TW37, a small-molecule inhibitor of Bcl-2. Cancer Res 2006; 66: 8698-706.
Andoniou CE, Andrews DM, Manzur M, Ricciardi-Castagnoli P and Degli-Esposti MA. A novel checkpoint in the Bcl-2-regulated apoptotic pathway revealed by murine cytomegalovirus infection of dendritic cells. J Cell Biol 2004; 166: 827-37.
Hu ZY, Zhu XF, Zhong ZD, Sun J, Wang J, Yang D, et al., ApoG2, a novel inhibitor of antiapoptotic Bcl-2 family proteins, induces apoptosis and suppresses tumor growth in nasopharyngeal carcinoma xenografts. Int J Cancer 2008; 123: 2418-29.
Vanasse GJ, Winn RK, Rodov S, Zieske AW, Li JT, Tupper JC, et al., Bcl-2 overexpression leads to increases in suppressor of cytokine signaling-3 expression in B cells and de novo follicular lymphoma. Mol Cancer Res 2004; 2: 620-31.
Del Vecchio S, Zannetti A, Aloj L, Caraco C, Ciarmiello A and Salvatore M. Inhibition of early 99mTc-MIBI uptake by Bcl-2 anti-apoptotic protein overexpression in untreated breast carcinoma. Eur J Nucl Med Mol Imaging 2003; 30: 879-87.
Badaracco G, Venuti A, Bartolazzi A, Morello R, Marzetti F and Marcante ML. Overexpression of p53 and bcl-2 proteins and the presence of HPV infection are independent events in head and neck cancer. J Oral Pathol Med 2000; 29: 173-9.
Grace VM, Shalini JV, lekha TT, Devaraj SN and Devaraj H. Co-overexpression of p53 and bcl-2 proteins in HPV-induced squamous cell carcinoma of the uterine cervix. Gynecol Oncol 2003; 91: 51-8.
Cervero C, Escribano L, San Miguel JF, Diaz-Agustin B, Bravo P, Villarrubia J, et al., Expression of Bcl-2 by human bone marrow mast cells and its overexpression in mast cell leukemia. Am J Hematol 1999; 60: 191-5.
Wang H, Zhang Z, Wei X and Dai R. Small-molecule inhibitor of Bcl-2 (TW-37) suppresses growth and enhances cisplatin-induced apoptosis in ovarian cancer cells. J Ovarian Res 2015; 8: 3.
Shi X, Dou Y, Zhou K, Huo J, Yang T, Qin T, et al., Targeting the Bcl-2 family and P-glycoprotein reverses paclitaxel resistance in human esophageal carcinoma cell line. Biomed Pharmacother 2017; 90: 897-905.
Li G, Liu L, Shan C, Cheng Q, Budhraja A, Zhou T, et al., RhoA/ROCK/PTEN signaling is involved in AT-101-mediated apoptosis in human leukemia cells in vitro and in vivo. Cell Death Dis 2014; 5: e998.
Sadahira K, Sagawa M, Nakazato T, Uchida H, Ikeda Y, Okamoto S, et al., Gossypol induces apoptosis in multiple myeloma cells by inhibition of interleukin-6 signaling and Bcl-2/Mcl-1 pathway. Int J Oncol 2014; 45: 2278-86.
Balakrishnan K, Wierda WG, Keating MJ and Gandhi V. Gossypol, a BH3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells. Blood 2008; 112: 1971-80.
Sun J, Li ZM, Hu ZY, Lin XB, Zhou NN, Xian LJ, et al., ApoG2 inhibits antiapoptotic Bcl-2 family proteins and induces mitochondria-dependent apoptosis in human lymphoma U937 cells. Anticancer Drugs 2008; 19: 967-74.
Voss V, Senft C, Lang V, Ronellenfitsch MW, Steinbach JP, Seifert V, et al., The pan-Bcl-2 inhibitor (-)-gossypol triggers autophagic cell death in malignant glioma. Mol Cancer Res 2010; 8: 1002-16.
He JH, Liao XL, Wang W, Li DD, Chen WD, Deng R, et al., Apogossypolone, a small-molecule inhibitor of Bcl-2, induces radiosensitization of nasopharyngeal carcinoma cells by stimulating autophagy. Int J Oncol 2014; 45: 1099-108.
Cheng P, Ni Z, Dai X, Wang B, Ding W, Rae Smith A, et al., The novel BH-3 mimetic apogossypolone induces Beclin-1- and ROS-mediated autophagy in human hepatocellular carcinoma cells. Cell Death Dis 2013; 4: e489.