Molecular and Cellular Biochemistry

, Volume 361, Issue 1–2, pp 47–54 | Cite as

1-Phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) facilitates curcumin-induced melanoma cell apoptosis by enhancing ceramide accumulation, JNK activation, and inhibiting PI3K/AKT activation

  • Teng Yu
  • Jinchao Li
  • Ying Qiu
  • Hui Sun


The majority of metastatic melanomas are resistant to different chemotherapeutic agents, consequently, the search for novel anti-melanoma agents and adjuvant is urgent. Here, we found that 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), an inhibitor of glycosphingolipid biosynthesis, enhanced curcumin-induced cell growth inhibition and apoptosis in two melanoma cell lines (WM-115 and B16). PDMP facilitated curcumin-induced ceramide accumulation; the latter contributed to melanoma cell apoptosis. PDMP also dramatically enhanced curcumin-induced c-Jun N-terminal kinase activation, which was important to melanoma cell apoptosis. Meanwhile, curcumin plus PDMP treatment largely inhibited the activation of pro-survival PI3K/AKT signal pathway. In conclusion, PDMP-sensitized curcumin-induced melanoma cell growth inhibition and apoptosis in vitro due to changes of multiple signal events. Combining PDMP with curcumin may represent a new therapeutic intervention against melanoma.


Curcumin PDMP Ceramide c-Jun N-terminal kinase (JNK) AKT Apoptosis Melanoma 



This study was supported by the Natural Science Foundation of Shandong Province.

Conflict of interest

The authors declare that there are no conflicts of interest.


  1. 1.
    Balch CM, Soong SJ, Gershenwald JE et al (2001) Prognostic factors analysis of 17, 600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 19:3622–3634PubMedGoogle Scholar
  2. 2.
    Balch CM, Buzaid AC, Soong SJ et al (2001) Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635–3648PubMedGoogle Scholar
  3. 3.
    Soengas MS, Lowe SW (2003) Apoptosis and melanoma chemoresistance. Oncogene 22:3138–3151PubMedCrossRefGoogle Scholar
  4. 4.
    Molife R, Hancock BW (2002) Adjuvant therapy of malignant melanoma. Crit Rev Oncol Hematol 44:81–102PubMedCrossRefGoogle Scholar
  5. 5.
    Goel A, Kunnumakkara AB, Aggarwal BB (2008) Curcumin as “Curecumin”: from kitchen to clinic. Biochem Pharmacol 75:787–809PubMedCrossRefGoogle Scholar
  6. 6.
    Sharma RA, Gescher AJ, Steward WP (2005) Curcumin: the story so far. Eur J Cancer 41:1955–1968PubMedCrossRefGoogle Scholar
  7. 7.
    Dhillon N, Aggarwal BB, Newman RA et al (2008) Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res 14:4491–4499PubMedCrossRefGoogle Scholar
  8. 8.
    Woo JH, Kim YH, Choi YJ et al (2003) Molecular mechanisms of curcumin-induced cytotoxicity: induction of apoptosis through generation of reactive oxygen species, down-regulation of Bcl-XL and IAP, the release of cytochrome c and inhibition of Akt. Carcinogenesis 24:1199–1208PubMedCrossRefGoogle Scholar
  9. 9.
    Aggarwal S, Ichikawa H, Takada Y et al (2006) Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBalpha kinase and Akt activation. Mol Pharmacol 69:195–206PubMedGoogle Scholar
  10. 10.
    Balasubramanian S, Eckert RL (2007) Curcumin suppresses AP1 transcription factor-dependent differentiation and activates apoptosis in human epidermal keratinocytes. J Biol Chem 282:6707–6715PubMedCrossRefGoogle Scholar
  11. 11.
    Moussavi M, Assi K, Gomez-Munoz A et al (2006) Curcumin mediates ceramide generation via the de novo pathway in colon cancer cells. Carcinogenesis 27:1636–1644PubMedCrossRefGoogle Scholar
  12. 12.
    Shukla A, Radin NS (1991) Metabolism of D-[3H]threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, an inhibitor of glucosylceramide synthesis, and the synergistic action of an inhibitor of microsomal monooxygenase. J Lipid Res 32:713–722PubMedGoogle Scholar
  13. 13.
    Ogretmen B, Hannun YA (2004) Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer 4:604–616PubMedCrossRefGoogle Scholar
  14. 14.
    Bleicher RJ, Cabot MC (2002) Glucosylceramide synthase and apoptosis. Biochim Biophys Acta 1585:172–178PubMedGoogle Scholar
  15. 15.
    Sietsma H, Veldman RJ, Kolk D et al (2000) 1-phenyl-2-decanoylamino-3-morpholino-1-propanol chemosensitizes neuroblastoma cells for taxol and vincristine. Clin Cancer Res 6:942–948PubMedGoogle Scholar
  16. 16.
    Hilchie AL, Furlong SJ, Sutton K et al (2010) Curcumin-induced apoptosis in PC3 prostate carcinoma cells is caspase-independent and involves cellular ceramide accumulation and damage to mitochondria. Nutr Cancer 62:379–389PubMedCrossRefGoogle Scholar
  17. 17.
    Yu T, Li J, Sun H (2010) C6 ceramide potentiates curcumin-induced cell death and apoptosis in melanoma cell lines in vitro. Cancer Chemother Pharmacol 66:999–1003PubMedCrossRefGoogle Scholar
  18. 18.
    Ji C, Yang Y, Yang B et al (2010) Trans-Zeatin attenuates ultraviolet induced down-regulation of aquaporin-3 in cultured human skin keratinocytes. Int J Mol Med 26:257–263PubMedGoogle Scholar
  19. 19.
    Sun H, Yu T, Li J (2011) Co-administration of perifosine with paclitaxel synergistically induces apoptosis in ovarian cancer cells: More than just AKT inhibition. Cancer Lett 310:118–128PubMedCrossRefGoogle Scholar
  20. 20.
    Radin NS, Shayman JA, Inokuchi J (1993) Metabolic effects of inhibiting glucosylceramide synthesis with PDMP and other substances. Adv Lipid Res 26:183–213PubMedGoogle Scholar
  21. 21.
    Collett GP, Campbell FC (2004) Curcumin induces c-jun N-terminal kinase-dependent apoptosis in HCT116 human colon cancer cells. Carcinogenesis 25:2183–2189PubMedCrossRefGoogle Scholar
  22. 22.
    Hay N (2005) The Akt-mTOR tango and its relevance to cancer. Cancer Cell 8:179–183PubMedCrossRefGoogle Scholar
  23. 23.
    Gopal YN, Deng W, Woodman SE et al (2010) Basal and treatment-induced activation of AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in braf-mutant human cutaneous melanoma cells. Cancer Res 70:8736–8747PubMedCrossRefGoogle Scholar
  24. 24.
    McKenzie JA, Liu T, Goodson AG et al (2010) Survivin enhances motility of melanoma cells by supporting Akt activation and {alpha} 5 integrin upregulation. Cancer Res 70:7927–7937PubMedCrossRefGoogle Scholar
  25. 25.
    Hannun YA (1997) Apoptosis and the dilemma of cancer chemotherapy. Blood 89:1845–1853PubMedGoogle Scholar
  26. 26.
    Mathias S, Pena LA, Kolesnick RN (1998) Signal transduction of stress via ceramide. Biochem J 335(Pt 3):465–480PubMedGoogle Scholar
  27. 27.
    Veldman RJ, Klappe K, Hoekstra D et al (1998) Metabolism and apoptotic properties of elevated ceramide in HT29rev cells. Biochem J 331(Pt 2):563–569PubMedGoogle Scholar
  28. 28.
    Babia T, Veldman RJ, Hoekstra D et al (1998) Modulation of carcinoembryonic antigen release by glucosylceramide–implications for HT29 cell differentiation. Eur J Biochem 258:233–242PubMedCrossRefGoogle Scholar
  29. 29.
    Bose R, Verheij M, Haimovitz-Friedman A et al (1995) Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell 82:405–414PubMedCrossRefGoogle Scholar
  30. 30.
    Jaffrezou JP, Levade T, Bettaieb A et al (1996) Daunorubicin-induced apoptosis: triggering of ceramide generation through sphingomyelin hydrolysis. EMBO J 15:2417–2424PubMedGoogle Scholar
  31. 31.
    Myrick D, Blackinton D, Klostergaard J et al (1999) Paclitaxel-induced apoptosis in Jurkat, a leukemic T cell line, is enhanced by ceramide. Leuk Res 23:569–578PubMedCrossRefGoogle Scholar
  32. 32.
    Yu T, Li J, Sun H (2010) C6 ceramide potentiates curcumin-induced cell death and apoptosis in melanoma cell lines in vitro. Cancer Chemother Pharmacol 66:999–1003PubMedCrossRefGoogle Scholar
  33. 33.
    Dobrowsky RT, Kamibayashi C, Mumby MC et al (1993) Ceramide activates heterotrimeric protein phosphatase 2A. J Biol Chem 268:15523–15530PubMedGoogle Scholar
  34. 34.
    Law B, Rossie S (1995) The dimeric and catalytic subunit forms of protein phosphatase 2A from rat brain are stimulated by C2-ceramide. J Biol Chem 270:12808–12813PubMedCrossRefGoogle Scholar
  35. 35.
    Wolff RA, Dobrowsky RT, Bielawska A et al (1994) Role of ceramide-activated protein phosphatase in ceramide-mediated signal transduction. J Biol Chem 269:19605–19609PubMedGoogle Scholar
  36. 36.
    Kishikawa K, Chalfant CE, Perry DK et al (1999) Phosphatidic acid is a potent and selective inhibitor of protein phosphatase 1 and an inhibitor of ceramide-mediated responses. J Biol Chem 274:21335–21341PubMedCrossRefGoogle Scholar
  37. 37.
    Anand P, Kunnumakkara AB, Newman RA et al (2007) Bioavailability of curcumin: problems and promises. Mol Pharm 4:807–818PubMedCrossRefGoogle Scholar
  38. 38.
    Bill MA, Bakan C, Benson DM Jr et al (2009) Curcumin induces proapoptotic effects against human melanoma cells and modulates the cellular response to immunotherapeutic cytokines. Mol Cancer Ther 8:2726–2735PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  1. 1.Jining Medical UniversityJiningPeople’s Republic of China
  2. 2.Shanghai Skin Diseases HospitalShanghaiPeople’s Republic of China
  3. 3.Department of DermatologyJining First People’s HospitalJiningPeople’s Republic of China
  4. 4.Central Lab, Jining First People’s HospitalJiningPeople’s Republic of China

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