BLOCKADE OF EPIDERMAL GROWTH FACTOR RECEPTOR, CYCLOXYGENASE-2 (COX-2) AND MAMMALIAN TARGET OF RAPAMYCIN (M-TOR) IN ANIMAL MODEL OF LUNG CANCER
Abstract
To explore the effectiveness and possible toxicity of the use of epidermal growth factor receptor inhibitor (EGFR Inhibitor), Celecoxib (COX2 inhibitor) and Sirolimus (m-TOR inhibitor) as single agents and drug combinations for the treatment of lung cancer in an experimental model. Lung cancer was induced in Balb-C mice by intraperitoneal injection urethane. Mice were treated with water (control) , Erlotinib (E) (50 mg/kg), Celecoxib (X) (50 mg/kg), Sirolimus (R) (2 mg/kg) given alone and in the following doublet and triplet combinations in the same dosages for 7 days. The number of pulmonary nodules in the combined treatment was significantly inhibited compared with control (p=0.010); E (p=0.028), EX (p=0.010), ERX (p=0.040) showed a smaller number of statistically significant nodules. Regarding coat changes we observe statistically significant differences among groups (p<0.001) where ERX and ER had a higher occurrence of this change. There was a higher incidence of skin rashes in groups: E (p<0.001), ER (p<0.0001), and ERX (p<0.001). Regarding weight we identify weight loss in the ERX (p=0.025). The combination of EGFR inhibitor, COX-2 inhibitor and m-TOR inhibitor had anti-tumor activity in experimental lung cancer. The combination of Celecoxib treatment with Erlotinib is a suggestion for decrease of dermatological events in patients. The combination of EGFR inhibitor and Sirolimus does not decrease the number of lung nodules and potentiates adverse events.
Keywords:
Experimental trials, Lung cancer, Erlotinib Hydrochloride, Cicloooxgenase-2, m- TOR inhibitorDOI
https://doi.org/10.25004/IJPSDR.2016.080601References
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25. Vujic I, Sanlorenzo M, Posch C, Esteve-Puig R, Yen AJ et al. Metformin and trametinib have synergistic effects on cell viability and tumor growth in NRAS mutant cancer. Oncotarget. 2014.
26. Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005; 8: 299-309.
27. Cury PM, Lichtenfels AJ, Reymão MS, Conceição GM, Capelozzi VL, Saldiva PHN, et al. Urban levels of air pollution modifies the progression of urethane-induced lung tumours in mice. Pathol Res Pract. 2000; 196: 627-633.
28. Paceli RB, Cala RN, Santos CHF, Cordeiro JA, Neivad CM, Nagamineb KK, Cury P M. The influence of physical activity in the progression of experimental lung cancer in mice. Pathology - Research and Practice. 2012; 208: 377-381.
29. Yarden Y. Sliwkowski MX. Untangling the Erb signaling network. Nat Rev Mol Cell Biol. 2001; 2: 127-137.
30. Juhász E, Kim JH, Klingelschmitt G, Walzer S. Effects of erlotinib first-line maintenance therapy versus placebo on the health-related quality of life of patients with metastatic non-small-cell lung cancer. Eur J Cancer. 2013; 49: 1205-1215.
31. Willians CS, Mann M, DuBois RN. The role of cyclooxygenases in inflammation, cancer and development. Oncogene. 1999; 18: 7908-1916.
32. Li G, Yang T, Yan J. Cyclooxygenase-2 increased the angiogenic and metastatic potential of tumor cells. Biochem Biophys Res Commun. 2002; 299: 886-90.
33. Sing-Ranger G, Mokbel K. The role of cyclooxigenase-2 (COX2) in breast cancer, and implications of cox-2 inhibition. Eur J Surg Oncol. 2002; 28:729-737.
34. Rothwell PM, Price JF, Fowkes FG, Zanchetti A, Roncaglioni MC, Tognoni G, Lee R, Belch JFF, Wilson M, Mehta Z, Meade TW. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. The Lancet. 2012; 379:1602-1612.
35. Rothwell PM, Wilson M, Price JF, Belch JFF, Meade TW, Ziyah Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incidence cancers during randomised controlled trials. The Lancet. 2012; 379:1591-1601.
36. Sugiura Y, Nemoto E, Kawai O, Ohkubo Y, Fusegawa H, Kaseda S. Skin rash by gefitinib is a sign of favorable outcomes for patients of advanced lung adenocarcinoma in Japanese patients. Springerplus. 2013; 2: 20- 22.
37. Baghel MS, Goswami K. Bcl-2 Targeted Structural Based Computer Aided Drug Design (CAAD) For Therapeutic Assessment of Ricin in Prostate Cancer. Int. J. Pharm. Sci. Drug Res. 2015; 7(2):168-171.
38. Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008; 372:1809-1818.
2. Cufer T, Ovcaricek T, O’Brien MER. Systemic therapy of advanced non-small cell lung cancer: Major-developments of the last 5-years. European Journal of Cancer. 2012; 49:1216-1225.
3. Hasegawa Y, Ando M, Maemondo M, Yamamoto S, Isa SI, Saka H, Kubo A, Kawaguchi T, Takada M, Rosell R, Kurata T, Ou SH. The Role of Smoking Status on the Progression-Free Survival of Non-Small-Cell Lung Cancer Patients Harboring Activating Epidermal Growth Factor Receptor (EGFR) Mutations Receiving First-Line EGFR Tyrosine Kinase Inhibitor Versus Platinum Double Chemotherapy: A Meta-Analysis of Prospective Randomized Trials. The Oncologist. 2015; 2014-0285.
4. Kilic A, Schuchert MJ, Luketich JD, Landreneau RJ, Hefnawy TE. Efficacy of Signal Pathway Inhibitors Alone and in Combination with Cisplatin Varies Between Human Non-Small Cell Lung Cancer Lines. Journal of Surgical Research. 2009; 154:9-12.
5. Pal SK, Figlin RA, Reckamp K. Targeted Therapies for Non-Small Lung Cancer: An Evolving. Mol Cancer Ther. 2010; 9:1931-1944.
6. Gao G, Ren S, Li A, Xu J, Xu Q, Su C, Guo J, Deng Q, Zhou C. Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is effective as first-line treatment of advanced non-small-cell lung cancer with mutated EGFR: A meta-analysis from six phase III randomized controlled trials. Int J Cancer. 2012; 131: E822-9.
7. Nakachi I, Naoki K, Soejima K, Kawada I, Watanabe H, Yasuda H, Nakayama S, Yoda S, Satomi R, Ikemura S, Terai H, Sato T. Ishizaka A, et al. The combination of multiple receptor tyrosine kinase inhibitor and mammalian target of rapamycin inhibitor overcomes erlotinib resistance in lung cancer cell lines through c-Met inhibition. Cancer. 2010; 116: 3903-9.
8. Liao BC, Lin CC, Yang JC. Second and third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer. Curr Opin Oncol. 2015.
9. Xia GH, Zeng Y, Fang Y, Yu SR, Wang L, Shi MQ, Sun WL, Huang XE, Chen J, Feng JF. Effect of EGFR-TKI retreatment following chemotherapy for advanced non-small cell lung cancer patients who underwent EGFR-TKI. Cancer Biol Med. 2014; 11: 270-6.
10. Doval D, Prabhash K, Patil S, Chaturvedi H, Goswami C, Vaid A, et al. Clinical and epidemiological study of EGFR mutations and EML4-ALK fusion genes among Indian patients with adenocarcinoma of the lung. Onco Targets Ther. 2015; 8:117-23.
11. Spaans JN, Goss GD. Epidermal growth factor receptor tyrosine kinase inhibitors in early-stage nonsmall cell lung cancer. Curr Opin Oncol. 2015.
12. Klenke FM, Abdollahi A, Bischof M, Gebhard MM, Ewerbeck V, Huber PE, Sckell A. Celecoxib Enhances Radiation Response of Secondary Bone Tumors of a Human Non-Small Cell Lung Cancer via Anti angiogenesis In Vivo. Strahlentherapie und Onkologie. 2011; 187: 45-51.
13. Jendrossek V. Targeting apoptosis pathways by Celecoxib in cancer. Cancer Letters. 2011.
14. Zaric J, Joseph JM, Tercier S, Sengstag T, Ponsonnet L, Delorenzi M, Ruegg C, Identification of MAGI1 as a tumor-suppressor protein induced by cyclooxygenase-2 inhibitors in colorectal cancer cells.Oncogene. 2012; 31: 48–59.
15. Fitzgerald GA, Patrono C. The coxibs, selective inhibitor of cyclooxygenase-2. N Engl J Méd. 2001; 345: 433-442.
16. Harris RC, Breyer MD. Physiological regulation of cyclooxygenase-2 in the kidney. Am J Physiol Renal Physiol. 2001; 281: 1-11.
17. Jones R. Nonsteroidal Anti-inflammatory drug prescribing: past, present and future. Am J Med. 2001; 110: 4s-7s.
18. Gottschalk A, Smith DS. New concepts in acte pain therapy: preemptive analgesia. Am Fam Physician. 2001; 63:1979-1984.
19. Brambilla E, Moreira LF, Serafini EP. Avaliação Imonoistoquímica da proteína Ciclooxigenase-2 nas neoplasias colorretais e sua relação com fatores patológicos prognósticos. Rev. bras. colo-proctol. 2007; 27: 256-263.
20. Gradilone A, Pulcinelli FM, Lotti LV, Martino S, Mattiello T, Frati L, Aglianò AM, Gazzaniga P. Celecoxib induces MRP in lung cancer cells: therapeutic implications. J Clin Oncol. 2007; 25: 4318-20.
21. Zhang X, Chen ZG, Choe MS, Lin Y, Sun SY, Wieand HS, et al. Tumor Growth Inhibition by Simultaneously Blocking Epidermal Growth Factor Receptor and Cyclooxygenase-2 in a Xenograft Model. Clinical Cancer Research. 2005; 11: 6261-6269.
22. Wislez M, Spencer ML, Izzo JG, Juroske DM, Balhara K, Cody DD, et al. Inhibition of Mammalian Target of Rapamycin Reverses Alveolar Epithelial Neoplasia Induced by Oncogenic K-ras. Cancer Res. 2005; 65: 3226-3235.
23. Franovic A, Holterman C E, Payette J, Lee S. Human cancers converge at the HIF-2α oncogenic axis. PNAS. 2009; 109: 21306-21311.
24. Ramalingam SS, Harvey RD, Saba N, Owonikoko TK, Kauh J, Shin DM, et al. Phase 1 and pharmacokinetic study of everolimus, a mammalian target of rapamycin inhibitor, in combination with docetaxel for recurrent/refractory nonsmall cell lung cancer. Cancer. 2010; 116: 3903-3909.
25. Vujic I, Sanlorenzo M, Posch C, Esteve-Puig R, Yen AJ et al. Metformin and trametinib have synergistic effects on cell viability and tumor growth in NRAS mutant cancer. Oncotarget. 2014.
26. Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005; 8: 299-309.
27. Cury PM, Lichtenfels AJ, Reymão MS, Conceição GM, Capelozzi VL, Saldiva PHN, et al. Urban levels of air pollution modifies the progression of urethane-induced lung tumours in mice. Pathol Res Pract. 2000; 196: 627-633.
28. Paceli RB, Cala RN, Santos CHF, Cordeiro JA, Neivad CM, Nagamineb KK, Cury P M. The influence of physical activity in the progression of experimental lung cancer in mice. Pathology - Research and Practice. 2012; 208: 377-381.
29. Yarden Y. Sliwkowski MX. Untangling the Erb signaling network. Nat Rev Mol Cell Biol. 2001; 2: 127-137.
30. Juhász E, Kim JH, Klingelschmitt G, Walzer S. Effects of erlotinib first-line maintenance therapy versus placebo on the health-related quality of life of patients with metastatic non-small-cell lung cancer. Eur J Cancer. 2013; 49: 1205-1215.
31. Willians CS, Mann M, DuBois RN. The role of cyclooxygenases in inflammation, cancer and development. Oncogene. 1999; 18: 7908-1916.
32. Li G, Yang T, Yan J. Cyclooxygenase-2 increased the angiogenic and metastatic potential of tumor cells. Biochem Biophys Res Commun. 2002; 299: 886-90.
33. Sing-Ranger G, Mokbel K. The role of cyclooxigenase-2 (COX2) in breast cancer, and implications of cox-2 inhibition. Eur J Surg Oncol. 2002; 28:729-737.
34. Rothwell PM, Price JF, Fowkes FG, Zanchetti A, Roncaglioni MC, Tognoni G, Lee R, Belch JFF, Wilson M, Mehta Z, Meade TW. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. The Lancet. 2012; 379:1602-1612.
35. Rothwell PM, Wilson M, Price JF, Belch JFF, Meade TW, Ziyah Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incidence cancers during randomised controlled trials. The Lancet. 2012; 379:1591-1601.
36. Sugiura Y, Nemoto E, Kawai O, Ohkubo Y, Fusegawa H, Kaseda S. Skin rash by gefitinib is a sign of favorable outcomes for patients of advanced lung adenocarcinoma in Japanese patients. Springerplus. 2013; 2: 20- 22.
37. Baghel MS, Goswami K. Bcl-2 Targeted Structural Based Computer Aided Drug Design (CAAD) For Therapeutic Assessment of Ricin in Prostate Cancer. Int. J. Pharm. Sci. Drug Res. 2015; 7(2):168-171.
38. Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008; 372:1809-1818.
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01-11-2016
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“BLOCKADE OF EPIDERMAL GROWTH FACTOR RECEPTOR, CYCLOXYGENASE-2 (COX-2) AND MAMMALIAN TARGET OF RAPAMYCIN (M-TOR) IN ANIMAL MODEL OF LUNG CANCER”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 8, no. 6, Nov. 2016, pp. 281-6, https://doi.org/10.25004/IJPSDR.2016.080601.
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How to Cite
“BLOCKADE OF EPIDERMAL GROWTH FACTOR RECEPTOR, CYCLOXYGENASE-2 (COX-2) AND MAMMALIAN TARGET OF RAPAMYCIN (M-TOR) IN ANIMAL MODEL OF LUNG CANCER”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 8, no. 6, Nov. 2016, pp. 281-6, https://doi.org/10.25004/IJPSDR.2016.080601.
