Abstract
Advanced malignant melanoma has a poor prognosis since chemotherapy is mostly ineffective because, in part, of the intrinsic and/or extrinsic resistance of melanoma cells to systemic treatment with antineoplastic agents. The reasons for the chemoresistant phenotype are currently unknown. The relevance of well-analyzed drug resistance mechanisms in melanoma such as intracellular and extracellular transport, drug resistance by induction of certain enzyme systems, and altered drug-target interaction is reviewed. It has been shown that most anticancer drugs kill susceptible cells through induction of apoptosis. Therefore, the significance of apoptotic deficiency caused by alteration in the apoptotic pathway is discussed in relation to specific molecules and apoptotic mechanisms like death-receptors, the Bcl-2 family, and the Hsp family of proteins. The complexity of the molecular variants involved in signal transduction along apoptotic pathways suggests that the cell may possess a variety of possibilities for regulating apoptosis and generating apoptosis deficiency. Thus apoptosis and apoptosis deficiency should be analyzed to understand the mechanisms of melanoma resistance.
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References
Ball NJ, Yohn JJ, Morelli JG, Norris DA, Golitz LE, Hoeffler JP (1994) Ras mutations in human melanoma: a marker of malignant progression. J Invest Dermatol 102(3):285–290
Beck WT, Danks MK, Wolverton JS, Granzen B, Chen M, Schmidt CA, Bugg BY, Friche E, Suttle DP (1993) Altered DNA topoisomerase II in multidrug resistance. Cytotechnology 11(2):115–119
Benathan M, Alvero Jackson H, Mooy AM, Scaletta C, Frenk E (1992) Relationship between melanogenesis, glutathione levels and melphalan toxicity in human melanoma cells. Melanoma Res 2(5–6):305–314
Bennett MR (1999) Mechanisms of p53-induced apoptosis. Biochem Pharmacol 58(7):1089–1095
Berger W, Hauptmann E, Elbling L, Vetterlein M, Kokoschka EM, Micksche M (1997) Possible role of the multidrug resistance-associated protein (MRP) in chemoresistance of human melanoma cells. Int J Cancer 71(1):108–115
Borst P, Evers R, Kool M, Wijnholds J (2000) A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst 92(16):1295–1302
Bruey JM, Ducasse C, Bonniaud P, Ravagnan L, Susin SA, Diaz-Latoud C, Gurbuxani S, Arrigo AP, Kroemer G, Solary E, Garrido C (2000) Hsp27 negatively regulates cell death by interacting with cytochrome c. Nat Cell Biol 2(9):645–652
Budihardjo I, Oliver H, Lutter M, Luo X, Wang X (1999) Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol 15:269–290
Bukau B, Horwich AL (1998) The Hsp70 and Hsp60 chaperone machines. Cell 92(3):351–366
Campain JA, Slovak ML, Schoenlein PV, Popescu NC, Gottesman MM, Pastan I (1995) Acquisition of multiple copies of a mutant topoisomerase II alpha allele by chromosome 17 aneuploidy is associated with etoposide resistance in human melanoma cell lines. Somat Cell Mol Genet 21(6):451–471
Creagh EM, Cotter TG (1999) Selective protection by hsp 70 against cytotoxic drug-, but not Fas-induced T-cell apoptosis. Immunology 97(1):36–44
Daugas E, Susin SA, Zamzami N, Ferri KF, Irinopoulou T, Larochette N, Prevost MC, Leber B, Andrews D, Penninger J, Kroemer G (2000) Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. FASEB J 14(5):729–739
Du CY, Fang M, Li YC, Li L, Wang XD (2000) Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102(1):33–42
Eliopoulos AG, Kerr DJ, Herod J, Hodgkins L, Krajewski S, Reed JC, Young LS (1995) The control of apoptosis and drug resistance in ovarian cancer: influence of p53 and Bcl-2. Oncogene 11(7):1217–1228
Fink D, Aebi S, Howell SB (1998) The role of DNA mismatch repair in drug resistance. Clin Cancer Res 4(1):1–6
Fulda S, Susin SA, Kroemer G, Debatin KM (1998) Molecular ordering of apoptosis induced by anticancer drugs in neuroblastoma cells. Cancer Res 58(19):4453–4460
Garrido C, Bruey JM, Fromentin A, Hammann A, Arrigo AP, Solary E (1999) HSP27 inhibits cytochrome c-dependent activation of procaspase-9. FASEB J 13(14):2061–2070
Garrido C, Fromentin A, Bonnotte B, Favre N, Moutet M, Arrigo AP, Mehlen P, Solary E (1998) Heat shock protein 27 enhances the tumorigenicity of immunogenic rat colon carcinoma cell clones. Cancer Res 58(23):5495–5499
Gottesman MM, Pastan I (1993) Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 62:385–427
Griffith TS, Chin WA, Jackson GC, Lynch DH, Kubin MZ (1998) Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells. J Immunol 161(6):2833–2840
Grossman D, McNiff JM, Li F, Altieri DC (1999) Expression and targeting of the apoptosis inhibitor, survivin, in human melanoma. J Invest Dermatol 113(6):1076–1081
Grottke C, Mantwill K, Dietel M, Schadendorf D, Lage H (2000) Identification of differentially expressed genes in human melanoma cells with acquired resistance to various antineoplastic drugs. Int J Cancer 88(4):535–546
Grover R, Wilson GD (1996) Bcl-2 expression in malignant melanoma and its prognostic significance. Eur J Surg Oncol 22(4):347–349
Hartmann A, Blaszyk H, Cunningham JS, McGovern RM, Schroeder JS, Helander SD, Pittelkow MR, Sommer SS, Kovach JS (1996) Overexpression and mutations of p53 in metastatic malignant melanomas. Int J Cancer 67(3):313–317
Helmbach H, Kern MA, Rossmann E, Renz K, Schadendorf D (2002) Drug-resistance towards etoposide and cisplatin in human melanoma cells is associated with different modulations of apoptotic pathways. J Invest Dermatol 118:923–932
Helmbach H, Rossmann E, Kern MA, Schadendorf D (2001) Drug-resistance in human melanoma. Int J Cancer 93(5):617–622
Houghton JA (1999) Apoptosis and drug response. Curr Opin Oncol 11(6):475–481
Jaattela M, Wissing D, Kokholm K, Kallunki T, Egeblad M (1998) Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases. EMBO J 17(21):6124–6134
Jansen B, Schlagbauer Wadl H, Brown BD, Bryan RN, van Elsas A, Muller M, Wolff K, Eichler HG, Pehamberger H (1998) bcl-2 antisense therapy chemosensitizes human melanoma in Scid mice. Nat Med 4(2):232–234
Jansen B, Schlagbauer Wadl H, Eichler HG, Wolff K, van Elsas A, Schrier PI, Pehamberger H (1997) Activated N-ras contributes to the chemoresistance of human melanoma in severe combined immunodeficiency (SCID) mice by blocking apoptosis. Cancer Res 57(3):362–365
Jansen B, Wacheck V, HeereRess E, Schlagbauer Wadl H, Hoeller C, Lucas T, Hoermann M, Hollenstein U, Wolff K, Pehamberger H (2000) Chemosensitisation of malignant melanoma by BCL2 antisense therapy. Lancet 356(9243):1728–1733
Jarvis WD, Grant S, Kolesnick RN (1996) Ceramide and the induction of apoptosis. Clin Cancer Res 2(1):1–6
Kaufmann SH, Earnshaw WC (2000) Induction of apoptosis by cancer chemotherapy. Exp Cell Res 256(1):42–49
Kavallaris M (1997) The role of multidrug resistance-associated protein (MRP) expression in multidrug resistance. Anticancer Drugs 8(1):17–25
Kern MA, Helmbach H, Artuc M, Karmann D, Jurgovsky K, Schadendorf D (1997) Human melanoma cell lines selected in vitro displaying various levels of drug resistance against cisplatin, fotemustine, vindesine or etoposide: modulation of proto-oncogene expression. Anticancer Res 17(6d):4359–4370
Konig J, Nies AT, Cui Y, Leier I, Keppler D (1999) Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. Biochim Biophys Acta 1461(2):377–394
Kroemer G, Reed JC (2000) Mitochondrial control of cell death. Nat Med 6(5):513–519
Lage H, Christmann M, Kern MA, Dietel M, Pick M, Kaina B, Schadendorf D (1999) Expression of DNA repair proteins hMSH2, hMSH6, hMLH1, O 6-methylguanine-DNA methyltransferase and N-methylpurine-DNA glycosylase in melanoma cells with acquired drug resistance. Int J Cancer 80(5):744–750
Lage H, Helmbach H, Dietel M, Schadendorf D (2000) Modulation of DNA topoisomerase II activity and expression in melanoma cells with acquired drug resistance. Br J Cancer 82(2):488–491
Li G, Bush JA, Ho VC (2000) p53-dependent apoptosis in melanoma cells after treatment with camptothecin. J Invest Dermatol 114(3):514–519
Li G, Tang L, Zhou X, Tron V, Ho V (1998) Chemotherapy-induced apoptosis in melanoma cells is p53 dependent. Melanoma Res 8(1):17–23
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91(4):479–489
Liu X, Zou H, Slaughter C, Wang X (1997) DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell 89(2):175–184
Los M, Herr I, Friesen C, Fulda S, Schulze Osthoff K, Debatin KM (1997) Cross-resistance of CD95-and drug-induced apoptosis as a consequence of deficient activation of caspases (ICE/Ced-3 proteases). Blood 90(8):3118–3129
McGovern VJ, Balch CM, Wilton GW (1985) Cutaneous Melanoma: Clinical Management and Treatment Results Worldwide. J.B. Lippincott, Philadelphia, PA, pp 29–42
Mehlen P, Schulze-Osthoff K, Arrigo AP (1996) Small stress proteins as novel regulators of apoptosis. Heat shock protein 27 blocks Fas/APO-1-and staurosporine-induced cell death. J Biol Chem 271(28):16510–16514
Middleton MR, Lee SM, Arance A, Wood M, Thatcher N, Margison GP (2000a) O6-methylguanine formation, repair protein depletion and clinical outcome with a 4 hr schedule of temozolomide in the treatment of advanced melanoma: results of a phase II study. Int J Cancer 88(3):469–473
Middleton MR, Lorigan P, Owen J, Ashcroft L, Lee SM, Harper P, Thatcher N (2000b) A randomized phase III study comparing dacarbazine, BCNU, cisplatin and tamoxifen with dacarbazine and interferon in advanced melanoma. Br J Cancer 82(6):1158–1162
Middleton MR, Lunn JM, Morris C, Rustin G, Wedge SR, Brampton MH, Lind MJ, Lee SM, Newell DR, Bleehen NM, Newlands ES, Calvert AH, Margison GP, Thatcher N (1998) O 6-methylguanine-DNA methyltransferase in pretreatment tumour biopsies as a predictor of response to temozolomide in melanoma. Br J Cancer 78(9):1199–1202
Miyake H, Hara I, Gohji K, Yamanaka K, Arakawa S, Kamidono S (1998) Enhancement of chemosensitivity in human bladder cancer cells by adenoviral-mediated p53 gene transfer. Anticancer Res 18(4c):3087–3092
Mosser DD, Caron AW, Bourget L, Meriin AB, Sherman MY, Morimoto RI, Massie B (2000) The chaperone function of hsp70 is required for protection against stress-induced apoptosis. Mol Cell Biol 20(19):7146–7159
Mouawad R, Khayat D, Soubrane C (2000) Plasma Fas ligand, an inducer of apoptosis, and plasma soluble Fas, an inhibitor of apoptosis, in advanced melanoma. Melanoma Res 10(5):461–467
Nessling M, Kern MA, Schadendorf D, Lichter P (1999) Association of genomic imbalances with resistance to therapeutic drugs in human melanoma cell lines. Cytogenet Cell Genet 87(3–4):286–290
Pandey P, Farber R, Nakazawa A, Kumar S, Bharti A, Nalin C, Weichselbaum R, Kufe D, Kharbanda S (2000) Hsp27 functions as a negative regulator of cytochrome c-dependent activation of procaspase-3. Oncogene 19(16):1975–1981
Petty R, Evans A, Duncan I, Kurbacher C, Cree I (1998) Drug resistance in ovarian cancer — the role of p53. Pathol Oncol Res 4(2):97–102
Raisova M, Bektas M, Wieder T, Daniel P, Eberle J, Orfanos CE, Geilen CC (2000) Resistance to CD95/Fas-induced and ceramide-mediated apoptosis of human melanoma cells is caused by a defective mitochondrial cytochrome c release. FEBS Lett 473(1):27–32
Rathmell JC, Thompson CB (1999) The central effectors of cell death in the immune system. Annu Rev Immunol 17:781–828
Reed JC (1995) Bcl-2: prevention of apoptosis as a mechanism of drug resistance. Hematol Oncol Clin North Am 9(2):451–473
Reed JC (1999) Dysregulation of apoptosis in cancer. J Clin Oncol 17(9):2941–2953
Ross MI, Balch CM (1991) The current management of cutaneous melanoma. Adv Surg 24:139–200
Rünger TM, Emmert S, Schadendorf D, Diem C, Epe B, Hellfritsch D (2000) Alterations of DNA repair in melanoma cell lines resistant to cisplatin, fotemustine, or etoposide. J Invest Dermatol 114(1):34–39
Saleh A, Srinivasula SM, Balkir L, Robbins PD, Alnemri ES (2000) Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat Cell Biol 2(8):476–483
Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME (1998) Two CD95 (APO-1/Fas) signaling pathways. EMBO J 17(6):1675–1687
Schadendorf D, Herfordt R, Czarnetzki BM (1995) P-glycoprotein expression in primary and metastatic malignant melanoma. Br J Dermatol 132(4):551–555
Schadendorf D, Jurgovsky K, Kohlmus CM, Czarnetzki BM (1995a) Glutathione and related enzymes in tumor progression and metastases of human melanoma. J Invest Dermatol 105(1):109–112
Schadendorf D, Makki A, Stahr C, van Dyck A, Wanner R, Scheffer GL, Flens MJ, Scheper R, Henz BM (1995b) Membrane transport proteins associated with drug resistance expressed in human melanoma. Am J Pathol 147(6):1545–1552
Schadendorf D, Worm M, Algermissen B, Kohlmus CM, Czarnetzki BM (1994) Chemosensitivity testing of human malignant melanoma. A retrospective analysis of clinical response and in vitro drug sensitivity. Cancer 73(1):103–108
Scriha P, Poland J, Kohl S, Schnölzer M, Helmbach H, Hütter G, Lage H, Schadendorf D (2002) Study of the development of chemoresistance in melanoma cell lines using proteomics. J Invest Dermatol (in revision)
Sellers WR, Fisher DE (1999) Apoptosis and cancer drug targeting. J Clin Invest 104(12):1655–1661
Selzer E, Schlagbauer Wadl H, Okamoto I, Pehamberger H, Potter R, Jansen B (1998) Expression of Bcl-2 family members in human melanocytes, in melanoma metastases and in melanoma cell lines. Melanoma Res 8(3):197–203
Serrone L, Hersey P (1999) The chemoresistance of human malignant melanoma: an update. Melanoma Res 9(1):51–58
Shin MS, Park WS, Kim SY, Kim HS, Kang SJ, Song KY, Park JY, Dong SM, Pi JH, Oh RR, Lee JY, Yoo NJ, Lee SH (1999) Alterations of Fas (Apo-1/CD95) gene in cutaneous malignant melanoma. Am J Pathol 154(6):1785–1791
Soengas MSPC, Polsky D, Mora J, Esteller M, Optiz-Araya X, McCombie R, Hermann JG, Gerald WL, Lazebnik YA, Cordon-Cardo C, Lowe SW (2001) Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature 409(11):207–211
Thomas WD, Hersey P (1998) TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in Fas ligand-resistant melanoma cells and mediates CD4 T cell killing of target cells. J Immunol 161(5):2195–2200
Ugurel S, Seiter S, Rappl G, Stark A, Tilgen W, Reinhold U (1999) Heterogenous susceptibility to CD95-induced apoptosis in melanoma cells correlates with bcl-2 and bcl-x expression and is sensitive to modulation by interferon-gamma. Int J Cancer 82(5):727–736
Xanthoudakis S, Roy S, Rasper D, Hennessey T, Aubin Y, Cassady R, Tawa P, Ruel R, Rosen A, Nicholson DW (1999) Hsp60 accelerates the maturation of pro-caspase-3 by upstream activator proteases during apoptosis. EMBO J 18(8):2049–2056
Zhang K, Mack P, Wong KP (1998) Glutathione-related mechanisms in cellular resistance to anticancer drugs. Int J Oncol 12(4):871–882
Zhang XD, Franco A, Myers K, Gray C, Nguyen T, Hersey P (1999) Relation of TNF-related apoptosis-inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma. Cancer Res 59(11):2747–2753
Zou H, Henzel WJ, Liu X, Lutschg A, Wang X (1997) Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3 [see comments]. Cell 90(3):405–413
Zou H, Li Y, Liu X, Wang X (1999) An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem 274(17):11549–11556
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Helmbach, H., Sinha, P., Schadendorf, D. (2003). Human Melanoma: Drug Resistance. In: Reinhold, U., Tilgen, W. (eds) Chemosensitivity Testing in Oncology. Recent Results in Cancer Research, vol 161. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-19022-3_9
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