Login to MyKarger

New to MyKarger? Click here to sign up.



Login with Facebook

Forgot your password?

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login
(Shibboleth or OpenAthens)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Original Paper

Open Access Gateway

NBM-T-BMX-OS01, an Osthole Derivative, Sensitizes Human Lung Cancer A549 Cells to Cisplatin through AMPK-Dependent Inhibition of ERK and Akt Pathway

Chen T.-J.a · Zhou Y.-F.b · Ning J.-J.c · Yang T.a · Ren H.a · Li Y.a · Zhang S.a · Chen M.-W.a

Author affiliations

aRespiratory Department, The First Affiliated Hospital, Xi'an Jiaotong University College of Medicine, bDepartment of Neurosurgery, Xijing Hospital, Fourth Military Medical University, cHua-shan Central Hospital of Xi'an, Xi'an, Shaanxi, China

Corresponding Author

Ming-Wei Chen,

Respiratory Department, The First Affiliated Hospital, Xi'an jiaotong University College

of Medicine, Xi'an, Shaanxi 710061,( China)

Tel. +86-29-85323338, Fax +86-29-85323339, E-Mail cmw_xjtu@163.com

Related Articles for ""

Cell Physiol Biochem 2015;36:893-906

Do you have an account?

Login Information





Contact Information











I have read the Karger Terms and Conditions and agree.



Abstract

Background: Drug combination therapies using cisplatin and natural products are common practice in the treatment of human lung cancer. Osthole is a natural compound extracted from a number of medicinal plants and has been shown to exert strong anticancer activities with low toxicity. Methods: In the present study, NBM-T-BMX-OS01 (BMX), derived from the semi-synthesis of osthole, was evaluated in cisplatin treated A549 cells to investigate its effect on cisplatin resistance in human lung cancer. The anticancer effect of BMX were measured by cell viablity‚ colony formation‚ TUNEL staining‚ flow cytometry and cell cycle assay. The fluorescence staining was performed to detect intracellular and mitochondrial reactive oxygen species (ROS) generation. Western blot analysis, antagonists pretreatment and small interfering RNA (siRNA) transfection were used to determine the potential mechanism. Results: It was found that, in comparison with single cisplatin treatment, the combination of BMX and cisplatin resulted in greater efficacy in inhibition of proliferation and colony formation, apoptosis induction and cell cycle arrest. The results of fluorescence staining showed that the combination effect of BMX and cisplatin was due to oxidative stress induced by mitochondrial ROS generation. In addition, BMX significantly attenuated the phosphorylation of ERK and Akt, two important pro-survival kinases. In contrast, BMX inhibited the activation of AMPK, and knockdown of AMPK using specific siRNA partially reversed BMX-induced inhibition of ERK and Akt, as well as its synthetic effects on cisplatin induced anticancer activity in A549 cells. Conclusion: Taken together, this study provides that BMX might modulate cisplatin resistance through AMPK-ERK and AMPK-Akt pathways. These results also support the role of BMX as a potential drug candidate for use in combination with cisplatin in the treatment of human lung cancer.

© 2015 S. Karger AG, Basel


References

  1. Cagle PT, Chirieac LR: Advances in treatment of lung cancer with targeted therapy. Arch Pathol Lab Med 2012;136:504-509.
  2. Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300.
  3. Custodio A, de Castro J: Strategies for maintenance therapy in advanced non-small cell lung cancer: current status, unanswered questions and future directions. Crit Rev Oncol Hematol 2012;82:338-360.
  4. Zhuo W, Wang Y, Zhuo X, Zhang Y, Ao X, Chen Z: Knockdown of Snail, a novel zinc finger transcription factor, via RNA interference increases A549 cell sensitivity to cisplatin via JNK/mitochondrial pathway. Lung Cancer 2008;62:8-14.
  5. Burris HA, 3rd: Shortcomings of current therapies for non-small-cell lung cancer: unmet medical needs. Oncogene 2009;28 Suppl 1:S4-13.
  6. Gebbia V, Oniga F, Agueli R, Paccagnella A: Treatment of advanced non-small cell lung cancer: chemotherapy with or without cisplatin? Ann Oncol 2006;17 Suppl 2:ii83-87.
  7. Gonzalez VM, Fuertes MA, Alonso C, Perez JM: Is cisplatin-induced cell death always produced by apoptosis? Mol Pharmacol 2001;59:657-663.
    External Resources
  8. Kartalou M, Essigmann JM: Mechanisms of resistance to cisplatin. Mutat Res 2001;478:23-43.
  9. Rosell R, Lord RV, Taron M, Reguart N: DNA repair and cisplatin resistance in non-small-cell lung cancer. Lung Cancer 2002;38:217-227.
  10. Chen T, Liu W, Chao X, Qu Y, Zhang L, Luo P, Xie K, Huo J, Fei Z: Neuroprotective effect of osthole against oxygen and glucose deprivation in rat cortical neurons: involvement of mitogen-activated protein kinase pathway. Neuroscience 2011;183:203-211.
  11. Zhang L, Jiang G, Yao F, He Y, Liang G, Zhang Y, Hu B, Wu Y, Li Y, Liu H: Growth inhibition and apoptosis induced by osthole, a natural coumarin, in hepatocellular carcinoma. PLoS One 2012;7:e37865.
  12. Nakamura T, Kodama N, Arai Y, Kumamoto T, Higuchi Y, Chaichantipyuth C, Ishikawa T, Ueno K, Yano S: Inhibitory effect of oxycoumarins isolated from the Thai medicinal plant Clausena guillauminii on the inflammation mediators, iNOS, TNF-alpha, and COX-2 expression in mouse macrophage RAW 264.7. J Nat Med 2009;63:21-27.
  13. Matsuda H, Tomohiro N, Ido Y, Kubo M: Anti-allergic effects of cnidii monnieri fructus (dried fruits of Cnidium monnieri) and its major component, osthol. Biol Pharm Bull 2002;25:809-812.
  14. Li XX, Hara I, Matsumiya T: Effects of osthole on postmenopausal osteoporosis using ovariectomized rats; comparison to the effects of estradiol. Biol Pharm Bull 2002;25:738-742.
  15. Liang HJ, Suk FM, Wang CK, Hung LF, Liu DZ, Chen NQ, Chen YC, Chang CC, Liang YC: Osthole, a potential antidiabetic agent, alleviates hyperglycemia in db/db mice. Chem Biol Interact 2009;181:309-315.
  16. Yang LL, Wang MC, Chen LG, Wang CC: Cytotoxic activity of coumarins from the fruits of Cnidium monnieri on leukemia cell lines. Planta Med 2003;69:1091-1095.
  17. Chou SY, Hsu CS, Wang KT, Wang MC, Wang CC: Antitumor effects of Osthol from Cnidium monnieri: an in vitro and in vivo study. Phytother Res 2007;21:226-230.
  18. Riviere C, Goossens L, Pommery N, Fourneau C, Delelis A, Henichart JP: Antiproliferative effects of isopentenylated coumarins isolated from Phellolophium madagascariense Baker. Nat Prod Res 2006;20:909-916.
  19. Yang D, Gu T, Wang T, Tang Q, Ma C: Effects of osthole on migration and invasion in breast cancer cells. Biosci Biotechnol Biochem 2010;74:1430-1434.
  20. Kao SJ, Su JL, Chen CK, Yu MC, Bai KJ, Chang JH, Bien MY, Yang SF, Chien MH: Osthole inhibits the invasive ability of human lung adenocarcinoma cells via suppression of NF-kappaB-mediated matrix metalloproteinase-9 expression. Toxicol Appl Pharmacol 2012;261:105-115.
  21. Chen T, Fei F, Jiang XF, Zhang L, Qu Y, Huo K, Fei Z: Down-regulation of Homer1b/c attenuates glutamate-mediated excitotoxicity through endoplasmic reticulum and mitochondria pathways in rat cortical neurons. Free Radic Biol Med 2012;52:208-217.
  22. Estornell E, Fato R, Pallotti F, Lenaz G: Assay conditions for the mitochondrial NADH:coenzyme Q oxidoreductase. FEBS Lett 1993;332:127-131.
  23. Ding D, Wei S, Song Y, Li L, Du G, Zhan H, Cao Y: Osthole exhibits anti-cancer property in rat glioma cells through inhibiting PI3K/Akt and MAPK signaling pathways. Cell Physiol Biochem 2013;32:1751-1760.
  24. Wu DW, Wu TC, Wu JY, Cheng YW, Chen YC, Lee MC, Chen CY, Lee H: Phosphorylation of paxillin confers cisplatin resistance in non-small cell lung cancer via activating ERK-mediated Bcl-2 expression. Oncogene 2013;10.1038/onc.2013.389.
  25. Wang M, Liu ZM, Li XC, Yao YT, Yin ZX: Activation of ERK1/2 and Akt is associated with cisplatin resistance in human lung cancer cells. J Chemother 2013;25:162-169.
  26. Douillard JY, Eckardt J, Scagliotti GV: Challenging the platinum combinations in the chemotherapy of NSCLC. Lung Cancer 2002;38:S21-28.
  27. Stewart DJ: Mechanisms of resistance to cisplatin and carboplatin. Crit Rev Oncol Hematol 2007;63:12-31.
  28. Zhang Y, Wang C, Wang H, Wang K, Du Y, Zhang J: Combination of Tetrandrine with cisplatin enhances cytotoxicity through growth suppression and apoptosis in ovarian cancer in vitro and in vivo. Cancer Lett 2011;304:21-32.
  29. Jafri SH, Glass J, Shi R, Zhang S, Prince M, Kleiner-Hancock H: Thymoquinone and cisplatin as a therapeutic combination in lung cancer: In vitro and in vivo. J Exp Clin Cancer Res 2010;29:87.
  30. Ji NF, Yao LS, Li Y, He W, Yi KS, Huang M: Polysaccharide of Cordyceps sinensis enhances cisplatin cytotoxicity in non-small cell lung cancer H157 cell line. Integr Cancer Ther 2011;10:359-367.
  31. Xu XM, Zhang Y, Qu D, Feng XW, Chen Y, Zhao L: Osthole suppresses migration and invasion of A549 human lung cancer cells through inhibition of matrix metalloproteinase-2 and matrix metallopeptidase-9 in vitro. Mol Med Rep 2012;6:1018-1022.
  32. Xu X, Zhang Y, Qu D, Jiang T, Li S: Osthole induces G2/M arrest and apoptosis in lung cancer A549 cells by modulating PI3K/Akt pathway. J Exp Clin Cancer Res 2011;30:33.
  33. Okamoto T, Kobayashi T, Yoshida S: Chemical aspects of coumarin compounds for the prevention of hepatocellular carcinomas. Curr Med Chem Anticancer Agents 2005;5:47-51.
  34. Aruoma OI, Grootveld M, Bahorun T: Free radicals in biology and medicine: from inflammation to biotechnology. Biofactors 2006;27:1-3.
  35. Finaud J, Lac G, Filaire E: Oxidative stress : relationship with exercise and training. Sports Med 2006;36:327-358.
  36. Sosa V, Moline T, Somoza R, Paciucci R, Kondoh H, ME LL: Oxidative stress and cancer: an overview. Ageing Res Rev 2013;12:376-390.
  37. Perse M: Oxidative stress in the pathogenesis of colorectal cancer: cause or consequence? Biomed Res Int 2013;2013:725710.
  38. Filaire E, Dupuis C, Galvaing G, Aubreton S, Laurent H, Richard R, Filaire M: Lung cancer: what are the links with oxidative stress, physical activity and nutrition. Lung Cancer 2013;82:383-389.
  39. Siddik ZH: Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 2003;22:7265-7279.
  40. Nishi M, Abe Y, Fujimori S, Hamamoto A, Inoue Y, Miyazaki N, Oida Y, Ikoma N, Ohnishi Y, Yamazaki H, Ueyama Y, Nakamura M: The modifier subunit of glutamate cysteine ligase relates to cisplatin resistance in human small cell lung cancer xenografts in vivo. Oncol Rep 2005;14:421-424.
  41. Rosell R, Cobo M, IsIa D, Sanchez JM, Taron M, Altavilla G, Santarpia M, Moran T, Catot S, Etxaniz O: Applications of genomics in NSCLC. Lung Cancer 2005;50:S33-40.
  42. Zhang B, Zhang K, Liu Z, Hao F, Wang M, Li X, Yin Z, Liang H: Secreted clusterin gene silencing enhances chemosensitivity of a549 cells to cisplatin through AKT and ERK1/2 pathways in vitro. Cell Physiol Biochem 2014;33:1162-1175.
  43. Chen T, Cao L, Dong W, Luo P, Liu W, Qu Y, Fei Z: Protective effects of mGluR5 positive modulators against traumatic neuronal injury through PKC-dependent activation of MEK/ERK pathway. Neurochem Res 2012;37:983-990.
  44. Chen T, Zhang L, Qu Y, Huo K, Jiang X, Fei Z: The selective mGluR5 agonist CHPG protects against traumatic brain injury in vitro and in vivo via ERK and Akt pathway. Int J Mol Med 2012;29:630-636.
  45. Shi Y, Chen L, Li J, Lv YL, Sun Q, Wang LX, Jiao SC: Prognostic and predictive values of pERK1/2 and pAkt-1 expression in non-small cell lung cancer patients treated with adjuvant chemotherapy. Tumour Biol 2011;32:381-390.
  46. Balmanno K, Cook SJ: Tumour cell survival signalling by the ERK1/2 pathway. Cell Death Differ 2009;16:368-377.
  47. Yoon H, Min JK, Lee JW, Kim DG, Hong HJ: Acquisition of chemoresistance in intrahepatic cholangiocarcinoma cells by activation of AKT and extracellular signal-regulated kinase (ERK)1/2. Biochem Biophys Res Commun 2011;405:333-337.
  48. Lee S, Choi EJ, Jin C, Kim DH: Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line. Gynecol Oncol 2005;97:26-34.
  49. Ohta T, Ohmichi M, Hayasaka T, Mabuchi S, Saitoh M, Kawagoe J, Takahashi K, Igarashi H, Du B, Doshida M, Mirei IG, Motoyama T, Tasaka K, Kurachi H: Inhibition of phosphatidylinositol 3-kinase increases efficacy of cisplatin in in vivo ovarian cancer models. Endocrinology 2006;147:1761-1769.
  50. Lorusso PM, Adjei AA, Varterasian M, Gadgeel S, Reid J, Mitchell DY, Hanson L, DeLuca P, Bruzek L, Piens J, Asbury P, Van Becelaere K, Herrera R, Sebolt-Leopold J, Meyer MB: Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol 2005;23:5281-5293.
  51. McCubrey JA, Abrams SL, Ligresti G, Misaghian N, Wong EW, Steelman LS, Basecke J, Troppmair J, Libra M, Nicoletti F, Molton S, McMahon M, Evangelisti C, Martelli AM: Involvement of p53 and Raf/MEK/ERK pathways in hematopoietic drug resistance. Leukemia 2008;22:2080-2090.
  52. Hardie DG: AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev 2011;25:1895-1908.
  53. Hardie DG, Carling D, Gamblin SJ: AMP-activated protein kinase: also regulated by ADP? Trends Biochem Sci 2011;36:470-477.
  54. Hardie DG: Sensing of energy and nutrients by AMP-activated protein kinase. Am J Clin Nutr 2011;93:891S-896.
  55. Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP, Alessi DR, Hardie DG: Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2003;2:28.
  56. Zheng B, Jeong JH, Asara JM, Yuan YY, Granter SR, Chin L, Cantley LC: Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol Cell 2009;33:237-247.
  57. William WN, Kim JS, Liu DD, Solis L, Behrens C, Lee JJ, Lippman SM, Kim ES, Hong WK, Wistuba, II, Lee HY: The impact of phosphorylated AMP-activated protein kinase expression on lung cancer survival. Ann Oncol 2012;23:78-85.
  58. Kim J, Yoon MY, Choi SL, Kang I, Kim SS, Kim YS, Choi YK, Ha J: Effects of stimulation of AMP-activated protein kinase on insulin-like growth factor 1- and epidermal growth factor-dependent extracellular signal-regulated kinase pathway. J Biol Chem 2001;276:19102-19110.
  59. Hwang JT, Kim YM, Surh YJ, Baik HW, Lee SK, Ha J, Park OJ: Selenium regulates cyclooxygenase-2 and extracellular signal-regulated kinase signaling pathways by activating AMP-activated protein kinase in colon cancer cells. Cancer Res 2006;66:10057-10063.
  60. Chou CC, Lee KH, Lai IL, Wang D, Mo X, Kulp SK, Shapiro CL, Chen CS: AMPK reverses the mesenchymal phenotype of cancer cells by targeting the Akt-MDM2-Foxo3a signaling axis. Cancer Res 2014;74:4783-4795.

Article / Publication Details

First-Page Preview
Abstract of Original Paper

Accepted: April 08, 2015
Published online: June 09, 2015
Issue release date: June 2015

Number of Print Pages: 14
Number of Figures: 7
Number of Tables: 0

ISSN: 1015-8987 (Print)
eISSN: 1421-9778 (Online)

For additional information: https://www.karger.com/CPB

References

  1. Cagle PT, Chirieac LR: Advances in treatment of lung cancer with targeted therapy. Arch Pathol Lab Med 2012;136:504-509.
  2. Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300.
  3. Custodio A, de Castro J: Strategies for maintenance therapy in advanced non-small cell lung cancer: current status, unanswered questions and future directions. Crit Rev Oncol Hematol 2012;82:338-360.
  4. Zhuo W, Wang Y, Zhuo X, Zhang Y, Ao X, Chen Z: Knockdown of Snail, a novel zinc finger transcription factor, via RNA interference increases A549 cell sensitivity to cisplatin via JNK/mitochondrial pathway. Lung Cancer 2008;62:8-14.
  5. Burris HA, 3rd: Shortcomings of current therapies for non-small-cell lung cancer: unmet medical needs. Oncogene 2009;28 Suppl 1:S4-13.
  6. Gebbia V, Oniga F, Agueli R, Paccagnella A: Treatment of advanced non-small cell lung cancer: chemotherapy with or without cisplatin? Ann Oncol 2006;17 Suppl 2:ii83-87.
  7. Gonzalez VM, Fuertes MA, Alonso C, Perez JM: Is cisplatin-induced cell death always produced by apoptosis? Mol Pharmacol 2001;59:657-663.
    External Resources
  8. Kartalou M, Essigmann JM: Mechanisms of resistance to cisplatin. Mutat Res 2001;478:23-43.
  9. Rosell R, Lord RV, Taron M, Reguart N: DNA repair and cisplatin resistance in non-small-cell lung cancer. Lung Cancer 2002;38:217-227.
  10. Chen T, Liu W, Chao X, Qu Y, Zhang L, Luo P, Xie K, Huo J, Fei Z: Neuroprotective effect of osthole against oxygen and glucose deprivation in rat cortical neurons: involvement of mitogen-activated protein kinase pathway. Neuroscience 2011;183:203-211.
  11. Zhang L, Jiang G, Yao F, He Y, Liang G, Zhang Y, Hu B, Wu Y, Li Y, Liu H: Growth inhibition and apoptosis induced by osthole, a natural coumarin, in hepatocellular carcinoma. PLoS One 2012;7:e37865.
  12. Nakamura T, Kodama N, Arai Y, Kumamoto T, Higuchi Y, Chaichantipyuth C, Ishikawa T, Ueno K, Yano S: Inhibitory effect of oxycoumarins isolated from the Thai medicinal plant Clausena guillauminii on the inflammation mediators, iNOS, TNF-alpha, and COX-2 expression in mouse macrophage RAW 264.7. J Nat Med 2009;63:21-27.
  13. Matsuda H, Tomohiro N, Ido Y, Kubo M: Anti-allergic effects of cnidii monnieri fructus (dried fruits of Cnidium monnieri) and its major component, osthol. Biol Pharm Bull 2002;25:809-812.
  14. Li XX, Hara I, Matsumiya T: Effects of osthole on postmenopausal osteoporosis using ovariectomized rats; comparison to the effects of estradiol. Biol Pharm Bull 2002;25:738-742.
  15. Liang HJ, Suk FM, Wang CK, Hung LF, Liu DZ, Chen NQ, Chen YC, Chang CC, Liang YC: Osthole, a potential antidiabetic agent, alleviates hyperglycemia in db/db mice. Chem Biol Interact 2009;181:309-315.
  16. Yang LL, Wang MC, Chen LG, Wang CC: Cytotoxic activity of coumarins from the fruits of Cnidium monnieri on leukemia cell lines. Planta Med 2003;69:1091-1095.
  17. Chou SY, Hsu CS, Wang KT, Wang MC, Wang CC: Antitumor effects of Osthol from Cnidium monnieri: an in vitro and in vivo study. Phytother Res 2007;21:226-230.
  18. Riviere C, Goossens L, Pommery N, Fourneau C, Delelis A, Henichart JP: Antiproliferative effects of isopentenylated coumarins isolated from Phellolophium madagascariense Baker. Nat Prod Res 2006;20:909-916.
  19. Yang D, Gu T, Wang T, Tang Q, Ma C: Effects of osthole on migration and invasion in breast cancer cells. Biosci Biotechnol Biochem 2010;74:1430-1434.
  20. Kao SJ, Su JL, Chen CK, Yu MC, Bai KJ, Chang JH, Bien MY, Yang SF, Chien MH: Osthole inhibits the invasive ability of human lung adenocarcinoma cells via suppression of NF-kappaB-mediated matrix metalloproteinase-9 expression. Toxicol Appl Pharmacol 2012;261:105-115.
  21. Chen T, Fei F, Jiang XF, Zhang L, Qu Y, Huo K, Fei Z: Down-regulation of Homer1b/c attenuates glutamate-mediated excitotoxicity through endoplasmic reticulum and mitochondria pathways in rat cortical neurons. Free Radic Biol Med 2012;52:208-217.
  22. Estornell E, Fato R, Pallotti F, Lenaz G: Assay conditions for the mitochondrial NADH:coenzyme Q oxidoreductase. FEBS Lett 1993;332:127-131.
  23. Ding D, Wei S, Song Y, Li L, Du G, Zhan H, Cao Y: Osthole exhibits anti-cancer property in rat glioma cells through inhibiting PI3K/Akt and MAPK signaling pathways. Cell Physiol Biochem 2013;32:1751-1760.
  24. Wu DW, Wu TC, Wu JY, Cheng YW, Chen YC, Lee MC, Chen CY, Lee H: Phosphorylation of paxillin confers cisplatin resistance in non-small cell lung cancer via activating ERK-mediated Bcl-2 expression. Oncogene 2013;10.1038/onc.2013.389.
  25. Wang M, Liu ZM, Li XC, Yao YT, Yin ZX: Activation of ERK1/2 and Akt is associated with cisplatin resistance in human lung cancer cells. J Chemother 2013;25:162-169.
  26. Douillard JY, Eckardt J, Scagliotti GV: Challenging the platinum combinations in the chemotherapy of NSCLC. Lung Cancer 2002;38:S21-28.
  27. Stewart DJ: Mechanisms of resistance to cisplatin and carboplatin. Crit Rev Oncol Hematol 2007;63:12-31.
  28. Zhang Y, Wang C, Wang H, Wang K, Du Y, Zhang J: Combination of Tetrandrine with cisplatin enhances cytotoxicity through growth suppression and apoptosis in ovarian cancer in vitro and in vivo. Cancer Lett 2011;304:21-32.
  29. Jafri SH, Glass J, Shi R, Zhang S, Prince M, Kleiner-Hancock H: Thymoquinone and cisplatin as a therapeutic combination in lung cancer: In vitro and in vivo. J Exp Clin Cancer Res 2010;29:87.
  30. Ji NF, Yao LS, Li Y, He W, Yi KS, Huang M: Polysaccharide of Cordyceps sinensis enhances cisplatin cytotoxicity in non-small cell lung cancer H157 cell line. Integr Cancer Ther 2011;10:359-367.
  31. Xu XM, Zhang Y, Qu D, Feng XW, Chen Y, Zhao L: Osthole suppresses migration and invasion of A549 human lung cancer cells through inhibition of matrix metalloproteinase-2 and matrix metallopeptidase-9 in vitro. Mol Med Rep 2012;6:1018-1022.
  32. Xu X, Zhang Y, Qu D, Jiang T, Li S: Osthole induces G2/M arrest and apoptosis in lung cancer A549 cells by modulating PI3K/Akt pathway. J Exp Clin Cancer Res 2011;30:33.
  33. Okamoto T, Kobayashi T, Yoshida S: Chemical aspects of coumarin compounds for the prevention of hepatocellular carcinomas. Curr Med Chem Anticancer Agents 2005;5:47-51.
  34. Aruoma OI, Grootveld M, Bahorun T: Free radicals in biology and medicine: from inflammation to biotechnology. Biofactors 2006;27:1-3.
  35. Finaud J, Lac G, Filaire E: Oxidative stress : relationship with exercise and training. Sports Med 2006;36:327-358.
  36. Sosa V, Moline T, Somoza R, Paciucci R, Kondoh H, ME LL: Oxidative stress and cancer: an overview. Ageing Res Rev 2013;12:376-390.
  37. Perse M: Oxidative stress in the pathogenesis of colorectal cancer: cause or consequence? Biomed Res Int 2013;2013:725710.
  38. Filaire E, Dupuis C, Galvaing G, Aubreton S, Laurent H, Richard R, Filaire M: Lung cancer: what are the links with oxidative stress, physical activity and nutrition. Lung Cancer 2013;82:383-389.
  39. Siddik ZH: Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 2003;22:7265-7279.
  40. Nishi M, Abe Y, Fujimori S, Hamamoto A, Inoue Y, Miyazaki N, Oida Y, Ikoma N, Ohnishi Y, Yamazaki H, Ueyama Y, Nakamura M: The modifier subunit of glutamate cysteine ligase relates to cisplatin resistance in human small cell lung cancer xenografts in vivo. Oncol Rep 2005;14:421-424.
  41. Rosell R, Cobo M, IsIa D, Sanchez JM, Taron M, Altavilla G, Santarpia M, Moran T, Catot S, Etxaniz O: Applications of genomics in NSCLC. Lung Cancer 2005;50:S33-40.
  42. Zhang B, Zhang K, Liu Z, Hao F, Wang M, Li X, Yin Z, Liang H: Secreted clusterin gene silencing enhances chemosensitivity of a549 cells to cisplatin through AKT and ERK1/2 pathways in vitro. Cell Physiol Biochem 2014;33:1162-1175.
  43. Chen T, Cao L, Dong W, Luo P, Liu W, Qu Y, Fei Z: Protective effects of mGluR5 positive modulators against traumatic neuronal injury through PKC-dependent activation of MEK/ERK pathway. Neurochem Res 2012;37:983-990.
  44. Chen T, Zhang L, Qu Y, Huo K, Jiang X, Fei Z: The selective mGluR5 agonist CHPG protects against traumatic brain injury in vitro and in vivo via ERK and Akt pathway. Int J Mol Med 2012;29:630-636.
  45. Shi Y, Chen L, Li J, Lv YL, Sun Q, Wang LX, Jiao SC: Prognostic and predictive values of pERK1/2 and pAkt-1 expression in non-small cell lung cancer patients treated with adjuvant chemotherapy. Tumour Biol 2011;32:381-390.
  46. Balmanno K, Cook SJ: Tumour cell survival signalling by the ERK1/2 pathway. Cell Death Differ 2009;16:368-377.
  47. Yoon H, Min JK, Lee JW, Kim DG, Hong HJ: Acquisition of chemoresistance in intrahepatic cholangiocarcinoma cells by activation of AKT and extracellular signal-regulated kinase (ERK)1/2. Biochem Biophys Res Commun 2011;405:333-337.
  48. Lee S, Choi EJ, Jin C, Kim DH: Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line. Gynecol Oncol 2005;97:26-34.
  49. Ohta T, Ohmichi M, Hayasaka T, Mabuchi S, Saitoh M, Kawagoe J, Takahashi K, Igarashi H, Du B, Doshida M, Mirei IG, Motoyama T, Tasaka K, Kurachi H: Inhibition of phosphatidylinositol 3-kinase increases efficacy of cisplatin in in vivo ovarian cancer models. Endocrinology 2006;147:1761-1769.
  50. Lorusso PM, Adjei AA, Varterasian M, Gadgeel S, Reid J, Mitchell DY, Hanson L, DeLuca P, Bruzek L, Piens J, Asbury P, Van Becelaere K, Herrera R, Sebolt-Leopold J, Meyer MB: Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol 2005;23:5281-5293.
  51. McCubrey JA, Abrams SL, Ligresti G, Misaghian N, Wong EW, Steelman LS, Basecke J, Troppmair J, Libra M, Nicoletti F, Molton S, McMahon M, Evangelisti C, Martelli AM: Involvement of p53 and Raf/MEK/ERK pathways in hematopoietic drug resistance. Leukemia 2008;22:2080-2090.
  52. Hardie DG: AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev 2011;25:1895-1908.
  53. Hardie DG, Carling D, Gamblin SJ: AMP-activated protein kinase: also regulated by ADP? Trends Biochem Sci 2011;36:470-477.
  54. Hardie DG: Sensing of energy and nutrients by AMP-activated protein kinase. Am J Clin Nutr 2011;93:891S-896.
  55. Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP, Alessi DR, Hardie DG: Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2003;2:28.
  56. Zheng B, Jeong JH, Asara JM, Yuan YY, Granter SR, Chin L, Cantley LC: Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol Cell 2009;33:237-247.
  57. William WN, Kim JS, Liu DD, Solis L, Behrens C, Lee JJ, Lippman SM, Kim ES, Hong WK, Wistuba, II, Lee HY: The impact of phosphorylated AMP-activated protein kinase expression on lung cancer survival. Ann Oncol 2012;23:78-85.
  58. Kim J, Yoon MY, Choi SL, Kang I, Kim SS, Kim YS, Choi YK, Ha J: Effects of stimulation of AMP-activated protein kinase on insulin-like growth factor 1- and epidermal growth factor-dependent extracellular signal-regulated kinase pathway. J Biol Chem 2001;276:19102-19110.
  59. Hwang JT, Kim YM, Surh YJ, Baik HW, Lee SK, Ha J, Park OJ: Selenium regulates cyclooxygenase-2 and extracellular signal-regulated kinase signaling pathways by activating AMP-activated protein kinase in colon cancer cells. Cancer Res 2006;66:10057-10063.
  60. Chou CC, Lee KH, Lai IL, Wang D, Mo X, Kulp SK, Shapiro CL, Chen CS: AMPK reverses the mesenchymal phenotype of cancer cells by targeting the Akt-MDM2-Foxo3a signaling axis. Cancer Res 2014;74:4783-4795.

Open Access License / Drug Dosage / Disclaimer

Open Access License: This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.