Antitumor activity of MEK and PI3K inhibitors against malignant pleural mesothelioma cells in vitro and in vivo

Miyoshi,Seigo; Hamada,Hironobu; Hamaguchi,Naohiko; Kato,Aki; Katayama,Hitoshi; Irifune,Kazunori; Ito,Ryoji; Miyazaki,Tatsuhiko; Okura,Takafumi; Higaki,Jitsuo

doi:10.3892/ijo.2012.1462

Antitumor activity of MEK and PI3K inhibitors against malignant pleural mesothelioma cells in vitro and in vivo

Authors:
- Seigo Miyoshi
- Hironobu Hamada
- Naohiko Hamaguchi
- Aki Kato
- Hitoshi Katayama
- Kazunori Irifune
- Ryoji Ito
- Tatsuhiko Miyazaki
- Takafumi Okura
- Jitsuo Higaki
View Affiliations

Affiliations: Department of Integrated Medicine and Informatics, Ehime University Graduate School of Medicine, Ehime, Japan, Department of Health and Sports Medical Sciences, Graduate School of Health Sciences, Hiroshima University, Hiroshima, Japan, Department of Pathogenomics, Ehime University Graduate School of Medicine, Ehime, Japan
Published online on: May 8, 2012 https://doi.org/10.3892/ijo.2012.1462
Pages: 449-456
Copyright: © Miyoshi et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive malignancy for which there is no approved targeted therapy. We examined the therapeutic efficacy of the mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) inhibitors against human MPM cell lines both in vitro and orthotopically inoculated into severe combined immunodeficient (SCID) mice. In addition, the molecular mechanisms of these agents were confirmed in vitro and in vivo. The MEK or the PI3K inhibitor suppressed MPM cell growth in vitro in a dose-dependent manner via induction of G1 cell cycle arrest and apoptosis. In addition, combined use of the MEK and PI3K inhibitors showed an additive or synergistic inhibitory effect on MPM cell growth compared to treatment with either individual drug. Treatment with MEK or PI3K inhibitor suppressed the production of thoracic tumors and pleural effusion and prolonged the survival time of EHMES-10 cell-bearing SCID mice. The combination therapy more effectively prolonged the survival time compared to treatment with either individual drug. Immunohistochemical and western blot analysis of thoracic tumors suggested that these agents induced cell cycle arrest, apoptosis and inhibition of tumor angiogenesis. Our results suggest that a combination of MEK and PI3K inhibitors is a promising therapeutic strategy for MPM.

View Figures

View References

1	Broaddus VC: Asbestos, the mesothelial cell and malignancy: a matter of life or death. Am J Respir Cell Mol Biol. 17:657–659. 1997. View Article : Google Scholar : PubMed/NCBI
2	Morinaga K, Kishimoto T, Sakatani M, Akira M, Yokoyama K and Sera Y: Asbestos-related lung cancer and mesothelioma in Japan. Ind Health. 39:65–74. 2001. View Article : Google Scholar : PubMed/NCBI
3	Dufresne A, Bégin R, Churg A and Massé S: Mineral fiber content of lungs in patients with mesothelioma seeking compensation in Quebec. Am J Respir Crit Care Med. 153:711–718. 1996. View Article : Google Scholar : PubMed/NCBI
4	Light RW: Primary tumors of the pleura: malignant mesotheliomas, solitary fibrous tumors, body cavity lymphoma, and pyothorax-associated lymphoma. Pleural Diseases. 4th edn. Lippincott Williams and Wilkins; Philadelphia, PA: pp. 135–150. 2001
5	Britton M: The epidemiology of mesothelioma. Semin Oncol. 29:18–25. 2002. View Article : Google Scholar : PubMed/NCBI
6	Zellos L and Sugarbaker DJ: Current surgical management of malignant pleural mesothelioma. Curr Oncol Rep. 4:354–360. 2002. View Article : Google Scholar : PubMed/NCBI
7	Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C and Paoletti P: Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 21:2636–2644. 2003. View Article : Google Scholar : PubMed/NCBI
8	Manning BD and Cantley LC: AKT/PKB signaling: navigating downstream. Cell. 129:1261–1274. 2007. View Article : Google Scholar : PubMed/NCBI
9	Marte BM and Downward J: PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond. Trends Biochem Sci. 22:355–358. 1997. View Article : Google Scholar : PubMed/NCBI
10	Roberts PJ and Der CJ: Targeting the Raf-MEK-ERK mitogen activated protein kinase cascade for the treatment of cancer. Oncogene. 26:3291–3310. 2007. View Article : Google Scholar : PubMed/NCBI
11	Sebolt-Leopold JS, Dudley DT, Herrera R, Van Becelaere K, Wiland A, Gowan RC, Tecle H, Barrett SD, Bridges A, Przybranowski S, Leopold WR and Saltiel AR: Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med. 5:810–816. 1999. View Article : Google Scholar : PubMed/NCBI
12	Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-i S, Wada H, Fujimoto J and Kohno M: Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene. 18:813–822. 1999. View Article : Google Scholar : PubMed/NCBI
13	de Melo M, Gerbase MW, Curran J and Pache JC: Phosphorylated extracellular signal-regulated kinases are significantly increased in malignant mesothelioma. J Histochem Cytochem. 54:855–861. 2006.PubMed/NCBI
14	Altomare DA, You H, Xiao GH, Ramos-Nino ME, Skele KL, De Rienzo A, Jhanwar SC, Mossman BT, Kane AB and Testa JR: Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth. Oncogene. 24:6080–6089. 2005. View Article : Google Scholar : PubMed/NCBI
15	Cole GW, Alleva AM, Zuo JT, Sehgal SS, Yeow WS, Schrump DS and Nguyen DM: Suppression of pro-metastasis phenotypes expression in malignant pleural mesothelioma by the PI3K inhibitor LY294002 or the MEK inhibitor U0126. Anticancer Res. 26:809–822. 2006.PubMed/NCBI
16	Yokoyama A, Kohno N, Fujino S, Hamada H, Inoue Y, Fujioka S and Hiwada K: Origin of heterogeneity of interleukin-6 (IL-6) levels in malignant pleural effusions. Oncol Rep. 1:507–511. 1994.PubMed/NCBI
17	Nakataki E, Yano S, Matsumori Y, Goto H, Kakiuchi S, Muguruma H, Bando Y, Uehara H, Hamada H, Kito K, Yokoyama A and Sone S: Novel orthotopic implantation of human malignant pleural mesothelioma (EHMES-10 cells) highly expressing vascular endothelial growth factor and its receptor. Cancer Sci. 97:183–191. 2006. View Article : Google Scholar
18	Rak-Mardyla A and Gregoraszczuk EL: ERK 1/2 and PI-3 kinase pathways as a potential mechanism of ghrelin action on cell proliferation and apoptosis in the porcine ovarian follicular cells. J Physiol Pharmacol. 61:451–458. 2010.PubMed/NCBI
19	Ciofani G, Ricotti L, Danti S, Moscato S, Nesti C, D’Alessandro D, Dinucci D, Chiellini F, Pietrabissa A, Petrini M and Menciassi A: Investigation of interactions between poly-L-lysine-coated boron nitride nanotubes and C2C12 cells: up-take, cytocompatibility, and differentiation. Int J Nanomedicine. 5:285–298. 2010. View Article : Google Scholar : PubMed/NCBI
20	Hamaguchi N, Hamada H, Miyoshi S, Irifune K, Ito R, Miyazaki T and Higaki J: In vitro and in vivo therapeutic efficacy of the PPAR-γ agonist troglitazone in combination with cisplatin against malignant pleural mesothelioma cell growth. Cancer Sci. 101:1955–1964. 2010.
21	Soga Y, Komori H, Miyazaki T, Arita N, Terada M, Kamada K, Tanaka Y, Fujino T, Hiasa Y, Matsuura B, Onji M and Nose M: Toll-like receptor 3 signaling induces chronic pancreatitis through the Fas/Fas ligand-mediated cytotoxicity. Tohoku J Exp Med. 217:175–184. 2009. View Article : Google Scholar : PubMed/NCBI
22	Wee S, Jagani Z, Xiang KX, Loo A, Dorsch M, Yao YM, Sellers WR, Lengauer C and Stegmeier F: PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res. 69:4286–4293. 2009. View Article : Google Scholar : PubMed/NCBI
23	Bedogni B, Welford SM, Kwan AC, Ranger-Moore J, Saboda K and Powell MB: Inhibition of phosphatidylinositol-3-kinase and mitogen-activated protein kinase kinase 1/2 prevents melanoma development and promotes melanoma regression in the transgenic TPRas mouse model. Mol Cancer Ther. 5:3071–3077. 2006. View Article : Google Scholar
24	Furuya F, Lu C, Willingham MC and Cheng SY: Inhibition of phosphatidylinositol 3-kinase delays tumor progression and blocks metastatic spread in a mouse model of thyroid cancer. Carcinogenesis. 28:2451–2458. 2007. View Article : Google Scholar : PubMed/NCBI
25	McCubrey JA, Steelman LS, Abrams SL, Lee JT, Chang F, Bertrand FE, Navolanic PM, Terrian DM, Franklin RA, D’Assoro AB, Salisbury JL, Mazzarino MC, Stivala F and Libra M: Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 46:249–279. 2006. View Article : Google Scholar : PubMed/NCBI
26	Mukohara T, Civiello G, Johnson BE and Janne PA: Therapeutic targeting of multiple signaling pathways in malignant pleural mesothelioma. Oncology. 68:500–510. 2005. View Article : Google Scholar : PubMed/NCBI
27	Robinson BW and Lake RA: Advances in malignant mesothelioma. N Engl J Med. 353:1591–603. 2005. View Article : Google Scholar : PubMed/NCBI
28	Li Q, Yano S, Ogino H, Wang W, Uehara H, Nishioka Y and Sone S: The therapeutic efficacy of anti vascular endothelial growth factor antibody, bevacizumab, and pemetrexed against orthotopically implanted human pleural mesothelioma cells in severe combined immunodeficient mice. Clin Cancer Res. 13:5918–5925. 2007. View Article : Google Scholar
29	Yano S, Shinohara H, Herbst RS, Kuniyasu H, Bucana CD, Ellis LM and Fidler IJ: Production of experimental malignant pleural effusions is dependent on invasion of the pleura and expression of vascular endothelial growth factor/vascular permeability factor by human lung cancer cells. Am J Pathol. 157:1893–1903. 2000. View Article : Google Scholar
30	Rexer BN, Ghosh R and Arteaga CL: Inhibition of PI3K and MEK: It is all about combinations and biomarkers. Clin Cancer Res. 15:4518–4520. 2009. View Article : Google Scholar : PubMed/NCBI
31	Rinehart J, Adjei AA, Lorusso PM, Waterhouse D, Hecht JR, Natale RB, Hamid O, Varterasian M, Asbury P, Kaldjian EP, Gulyas S, Mitchell DY, Herrera R, Sebolt-Leopold JS and Meyer MB: Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol. 22:4456–4462. 2004. View Article : Google Scholar : PubMed/NCBI
32	Hu L, Zaloudek C, Mills GB, Gray J and Jaffe RB: In vivo and in vitro ovarian carcinoma growth inhibition by a phosphatidylinositol 3-kinase inhibitor (LY294002). Clin Cancer Res. 6:880–886. 2000.PubMed/NCBI
33	Hu L, Hofmann J, Lu Y, Mills GB and Jaffe RB: Inhibition of phosphatidylinositol 3′-kinase increases efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Cancer Res. 62:1087–1092. 2002.