Abstract
Although PS-341 (bortezomib) is a promising agent to improve multiple myeloma (MM) patient outcome, 65% of patients with relapsed and refractory disease do not respond. We have previously shown that heat shock protein (Hsp)27 is upregulated after PS-341 treatment, that overexpression of Hsp27 confers PS-341 resistance, and that inhibition of Hsp27 overcomes PS-341 resistance. Since Hsp27 is a downstream target of p38 mitogen-activated protein kinase (MAPK)/MAPK-mitogen-activated protein kinase-2 (MAPKAPK2), we hypothesized that inhibition of p38 MAPK activity could augment PS-341 cytotoxicity by downregulating Hsp27. Although p38 MAPK inhibitor SCIO-469 (Scios Inc, CA, USA) alone did not induce significant growth inhibition, it blocked baseline and PS-341-triggered phosphorylation of p38 MAPK as well as upregulation of Hsp27, associated with enhanced cytotoxicity in MM.1S cells. Importantly, SCIO-469 enhanced phosphorylation of c-Jun NH2-terminal kinase (JNK) and augmented cleavage of caspase-8 and poly(ADP)-ribose polymerase. Moreover, SCIO-469 downregulated PS-341-induced increases in G2/M-phase cells, associated with downregulation of p21Cip1 expression. Importantly, SCIO-469 treatment augmented cytotoxicity of PS-341 even against PS-341-resistant cell lines and patient MM cells. These studies therefore provide the framework for clinical trials of SCIO-469 to enhance sensitivity and overcome resistance to PS-341, thereby improving patient outcome in MM.
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References
Beyaert R, Cuenda A, Vanden Berghe W, Plaisance S, Lee JC, Haegeman G, Cohen P and Fiers W . (1996). EMBO J., 15, 1914–1923.
Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Cilberto G, Moscinski L, Fernandez-Luna JL, Nunez G, Dalton WS and Jove R . (1999). Immunity, 10, 105–115.
Chauhan D, Li G, Hideshima T, Podar K, Mitsiades C, Mitsiades N, Catley L, Tai YT, Hayashi T, Shringharpure R, Burger R, Munshi N, Ohtake Y, Saxena S and Anderson KC . (2003a). Blood, 102, 3379–3386.
Chauhan D, Li G, Hideshima T, Podar K, Mitsiades C, Mitsiades N, Munshi N, Kharbanda S and Anderson KC . (2003b). J. Biol. Chem., 278, 17593–17596.
Chauhan D, Li G, Podar K, Hideshima T, Shringarpure R, Catley L, Mitsiades C, Munshi N, Tai YT, Suh N, Gribble GW, Honda T, Schlossman R, Richardson P, Sporn MB and Anderson KC . (2004). Blood, 103, 3158–3166.
Chauhan D, Li G, Shringarpure R, Podar K, Ohtake Y, Hideshima T and Anderson KC . (2003c). Cancer Res., 63, 6174–6177.
Chauhan D, Uchiyama H, Akbarali Y, Urashima M, Yamamoto K, Libermann TA and Anderson KC . (1996). Blood, 87, 1104–1112.
Christians U, Jacobsen W, Benet LZ and Lampen A . (2002). Clin. Pharmacokinet., 41, 813–851.
Craig R, Larkin A, Mingo AM, Thuerauf DJ, Andrews C, McDonough PM and Clembotski CC . (2000). J. Biol. Chem., 275, 23814–23824.
Creagh EM, Sheehan D and Cotter TG . (2000). Leukemia, 14, 1161–1173.
Dalton WS and Jove R . (1999). Semin. Oncol., 26, 23–27.
Guay J, Lambert H, Gingras-Breton G, Lavoie JN, Huot J and Landry J . (1997). J. Cell. Sci., 110, 357–368.
Herrmann JL, Briones F, Brisbay S, Logothetis CJ and McDonnell TJ . (1998). Oncogene, 17, 2889–2899.
Hideshima T, Akiyama M, Hayashi T, Richardson P, Schlossman R, Chauhan D and Anderson KC . (2003a). Blood, 101, 703–705.
Hideshima T and Anderson KC . (2002). Nat. Rev. Cancer, 2, 927–937.
Hideshima T, Chauhan D, Hayashi T, Akiyama M, Mitsiades N, Mitsiades C, Podar K, Munshi NC, Richardson PG and Anderson KC . (2003b). Oncogene, 22, 8386–8393.
Hideshima T, Chauhan D, Hayashi T, Podar K, Akiyama M, Mitsiades C, Mitsiades N, Gong B, Bonham L, de Vries P, Munshi N, Richardson PG, Singer JW and Anderson KC . (2003c). Cancer Res., 63, 8428–8436.
Hideshima T, Chauhan D, Schlossman RL, Richardson PR and Anderson KC . (2001a). Oncogene, 20, 4519–4527.
Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai Y-T, Treon S, Lin B, Schlossman RL, Ridhardson P, Muller G, Stirling DI and Anderson KC . (2000). Blood, 96, 2943–2950.
Hideshima T, Hayashi T, Chauhan D, Akiyama M, Richardson P and Anderson K . (2003d). Oncogene, 22, 8797–8801.
Hideshima T, Mitsiades C, Akiyama M, Hayashi T, Chauhan D, Richardson P, Schlossman R, Podar K, Munshi NC, Mitsiades N and Anderson KC . (2003e). Blood, 101, 1530–1534.
Hideshima T, Nakamura N, Chauhan D and Anderson KC . (2001b). Oncogene, 20, 5991–6000.
Hideshima T, Richardson P, Chauhan D, Palombella V, Elliott P, Adams J and Anderson KC . (2001c). Cancer Res., 61, 3071–3076.
Huot J, Houle F, Marceau F and Landry J . (1997). Circ. Res., 80, 383–392.
Jolly C and Morimoto RI . (2000). J. Natl. Cancer Inst., 92, 1564–1572.
Jourdan M, Veyrune JL, Vos JD, Redal N, Couderc G and Klein B . (2003). Oncogene, 22, 2950–2959.
Kisselv AF and Goldberg AL . (2001). Chem. Biol., 21, 1–20.
Landry J and Huot J . (1995). Biochem. Cell Biol., 73, 703–707.
LeBlanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N, Neuberg D, Goloubeva O, Pien CS, Adams J, Gupta D, Richardson PG, Munshi N and Anderson KC . (2002). Cancer Res., 62, 4996–5000.
Lopes UG, Erhardt P, Yao R and Cooper GM . (1997). J. Biol. Chem., 272, 12893–12896.
Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Gu X, Bailey C, Joseph M, Libermann TA, Treon SP, Munshi NC, Richardson PG, Hideshima T and Anderson KC . (2002). Proc. Natl. Acad. Sci. USA, 99, 14374–14379.
Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M, Libermann TA, Schlossman R, Munshi NC, Hideshima T and Anderson KC . (2003). Blood, 101, 2377–2380.
Neumann C, Zehentmaier G, Danhauser-Riedl S, Emmerich B and Hallek M . (1996). Eur. J. Immunol., 26, 379–384.
New L, Jiang Y, Zhao M, Liu K, Zhu W, Flood LJ, Kato Y, Parry GC and Han J . (1998). EMBO J., 15, 3372–3384.
Ogata A, Chauhan D, Teoh G, Treon SP, Urashima M, Schlossman RL and Anderson KC . (1997). J. Immunol., 159, 2212–2221.
Orlowski RZ, Voorhees PM, Garcia RA, Hall MD, Lehman MJ, Johri A, Humes E, Adams J, Esseltine DL, Gabriel DA, Shea TC, Van Deventer HW, Mitchell BS and Dees C . (2003). Blood, 102, 449a.
Puthier D, Bataille R and Amiot M . (1999). Eur. J. Immunol., 29, 3945–3950.
Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP and Anderson KC . (2003). N. Engl. J. Med., 348, 2609–2617.
Schwarzenbach H . (2002). Med. Oncol., 19, 87–104.
Shieh S-Y, Ikeda M, Taya Y and Prives C . (1997). Cell, 91, 325–334.
Sun J, Nam S, Lee CS, Li B, Coppola D, Hamilton AD, Dou QP and Sebti SM . (2001). Cancer Res., 61, 1280–1284.
Tibbles LA, Ing YL, Kiefer F, Chan J, Iscove N, Woodgett JR and Lassam NJ . (1996). EMBO J., 15, 7026–7035.
Tu Y, Gardner A and Lichtenstein A . (2000). Cancer Res., 60, 6763–6770.
Uchiyama H, Barut BA, Mohrbacher AF, Chauhan D and Anderson KC . (1993). Blood, 82, 3712–3720.
Vanden Berghe W, Plaisance S, Boone E, De Bosscher K, Schmitz ML, Fiers W and Haegeman G . (1998). J. Biol. Chem., 273, 3285–3290.
Xanthoudakis S and Nicholson DW . (2000). Nat. Cell. Biol., 2, 163–165.
Yang HH, Swift R, Sadler K, Vescio R, Adams J, Schenkein D and Berenson JR . (2003). Blood, 102, 235a.
Zhang B, Gojo I and Fenton RG . (2002). Blood, 99, 1885–1893.
Acknowledgements
We thank Sarvajit Chakravarty, Sundeep Dugar, Gregory Leudtke, Babu Mavunkel, John Perumattam, Greg Luedtke, Sundeep Dugar, and Sarvajit Chakravarty for SCIO-469. This study is supported by Scios Fellowship in Multiple Myeloma Research (TH), National Institutes of Health Grants Specialized Programs of Research Excellence (SPORE) IP50 CA10070-01, PO-1 78378 and RO-1 CA 50947; the Doris Duke Distinguished Clinical Research Scientist Award (KCA); the Multiple Myeloma Research Foundation (TH); and the Cure for Myeloma Research Fund (KCA).
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Hideshima, T., Podar, K., Chauhan, D. et al. p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells. Oncogene 23, 8766–8776 (2004). https://doi.org/10.1038/sj.onc.1208118
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DOI: https://doi.org/10.1038/sj.onc.1208118
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