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Drug Resistance in Melanoma: New Perspectives Caterina A.M. La Porta* Department of Biomolecular Science and Biotechnology, University of Milan, Italy Abstract: Melanoma is the most aggressive form of skin cancer and advantages stages are inevitably resistant to conventional therapeutic agents. In particular, the inability of undergo apoptosis in response to chemotherapy and other external stimuli poses a selective advantage for tumor progression, metastasis formation as well as resistance to therapy in melanoma. Herein, we will review the discovery of MDR transporters and the apoptotic mechanisms used by melanoma cells. Furthermore, the novel strategies to overcome tumor chemoresistance will also discuss. In particular, we will review the cancer stem cell hypothesis and how the failure of MDR reversal agents might increase the therapeutic index of substrate antineoplastic agents.

MELANOMA AND CHEMORESISTANCE The incidence of cutaneous melanoma has been rising continuously over the last decades [1], although this might be due to an increased diagnostic scrutiny rather than a real increase in the incidence of the disease [2, 3] Early detection, and improved surgical techniques have led to an absolute gain in melanoma survival. Unfortunately, the systemic treatment has not modified the prognosis of patients with disseminated disease. Dacarbazine, vindesine, cisplatin, fotemustine and temozolomide are still the most commonly applied chemotherapeutics for metastatic melanoma [4, 5] (Fig. 1 shows the comparison between the chemical structure of dacarbazine and temozolomide); however, only a minority of patients responds and the survival benefit derived from these drugs is extremely limited [6]. In fact, the complete response rates with dacarbazine (DITC), the only drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic melanoma, rarely exceed 5% [7]. Moreover, combination cocktails of DITC with agents aimed to kill tumor cells by alkylation, cross-linking, ribonucleotide depletion, microtubule destabilization or topoisomerase inhibition, among others have failed to guarantee significantly long-term survival of patients with metastatic disease [8, 9]. CONH2 N H

N N O

N

N

N

NMe3

dacarbazine

NH2

N N

O temozolomide

Fig. (1). Chemical structures of dacarbazine and temozolomide.

*Address correspondence to this author at the Department of Biomolecular Science and Biotechnology, University of Milan, Italy; E-mail: [email protected] 0929-8673/07 $50.00+.00

Cancer chemotherapy efficacy is frequently impaired by either intrinsic or acquired tumor resistance, a phenomenon termed multi-drug resistance (MDR) [10]. MDR can result from several distinct mechanisms, including alterations of tumor cell cycle checkpoints, impairment of tumor apoptotic pathways, repair of damage cellular targets and reduced drug accumulation in tumor cells [10]. In the present review, recent developments about MDR transporters and the anti-apoptotic mechanisms used by melanoma will be discussed. MDR Transporter and Melanoma In analogy with the study of antibiotic resistance in microorganisms, the research on drug resistance in cancer has focused on cellular resistance due to either the specific nature and genetic background of the cancer cell itself, or the genetic changes that follow toxic chemotherapy. Until recently the primary, method for identifying surviving cancer cells in the presence of cytotoxic drugs was to use cellular and molecular biology techniques. The latter was used to identify altered genes that confer drug resistance on naïve cells. Such studies indicate that there are three major mechanisms of drug resistance in cells: first, decreased uptake of water-soluble drugs such as folate antagonists, nucleoside analogs and cisplatin, which require transporters to enter cells; second, changes in cells that affect the capacity of cytotoxic drugs to kill cells, including alterations in cell cycle, increased repair of DNA damage, reduced apoptosis and altered metabolism of drugs; and, third, increased energydependent efflux of hydrophobic drugs that can easily enter the cells by diffusion through the plasma membrane. Of these mechanisms, the one that is most commonly encountered in the laboratory is the increased efflux of a broad class of hydrophobic cytotoxic drugs that is mediated by one of a family of energy-dependent transporters, known as ATPbinding cassette (ABC) transporters. First described in the 1970s, ABC transporters are conserved proteins that typically translocate solutes across the cellular membranes [11]. The human genome contains 48 genes that encode ABC transporters, which have been divided into seven subfamilies labeled A-G [12]. Although several members of the super© 2007 Bentham Science Publishers Ltd.

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family have dedicated peculiar functions involving the transport of specific substrates, it is becoming increasingly evident that the complex physiological network of ABC transporters has a pivotal role in host detoxification and protection of the body against xenobiotics. Thereby, among the human ABC superfamily, only ABCB1, ABCC1 (MDR1) and ABCG2 have to date shown to mediate MDR, each with distinct, yet overlapping efflux substrate specificities and tissue distribution patterns [13]; fulfilling their role in detoxification, several ABC transporters have been found to be overexpressed in cancer cell lines cultured under selective pressure. In human melanoma, the role of ABCB1 (MDR1/Pglycoprotein), a well-characterized multidrug transporter belonging to the ABCB subfamily (MDR/TAP), which includes 11 members, appears to be limited [14]. ABCB5 is the third member of the human P-gp family next to its structural analogs ABCB1 [15-18] and ABCB4 [17]. ABCB5 is expressed in clinical malignant melanoma tumors and preferentially marks a subset of hyperpolarized CD133+ cells [19]. Furthermore, ABCB5 was demonstrated to reverse resistance of G3361 melanoma cells to doxorubicin, an agent to which clinical melanomas have been found to be refractory [20]. Therefore, ABCB5 appears to be a novel chemoresistance mediator in human melanoma. Recently, two novel isoforms, ABCB5alpha and ABCB5beta, were identified both in melanoma cells, melanocytes and retinal pigment epithelial cells, suggesting that they might be involved in melanogenesis [21]. Interestingly, it has been shown that an siRNA directed at ABCB5beta can reduce ABCB5beta mRNA levels and induce drug sensitivity to several drugs including camptothecin 10-OH, 5-FU and mitoxantrone in melanoma cells [22]. These data suggest that elevated ABCB5 expression may confer drug resistance to these agents. However, since ABCB5beta is not expressed in two multidrug resistant melanoma cell lines, it might have a distinct transport function as well [22]. ABCG2 is the second member of the G family of ABC transporters, which is identical to the placental ABC protein (ABCP1) [23], mitoxantrone-resistance protein (MXR) [24] and the breast cancer-resistance protein (BCRP1) [25] (Fig. 2). It clearly has the potential to contribute to the drug resistance of cancer cells. Furthermore, ABCG2 was demonstrated to be overexpressed in several cell lines selected for anticancer drug resistance and showed a high-capacity

Caterina A.M. La Porta

transporter with wide substrate specificity [26, 27]. Although several ABC transporters can transport methotrexate, ABCG2 has been shown to extrude glutamate folates, suggesting that it can provide resistance to both short- and long—term methotrexate exposure [28]. In addition, ABCG2 can transport some of the most recently developed anticancer drugs such as 7-ethyl-10-hydroxycamptothecin (SN-38) [29] (Fig. 3 shows the comparison between the chemical structure of methotrexate and SN-38) or tyrosine kinase inhibitors [30]. Interestingly, recently, melanoma biopsy as well as neuroendocrine carcinomas of the skin were found to be negative for ABCG2 [31]. NH2 N

N

N

NH2 N

O NH methotrexate

OH

N O

HO O

HO

O N N O OH

SN-38

O

Fig. (3). A membrane topology model of BCRP. BCRP contains one nucleotide binding domain (NBD) followed by one membranespanning domain (MSD) with 6 predicted transmembrane helices. Two or 3 putative N-glycosylation sites (N418, N557, or N596) are predicted to be in the extracellular loops as indicated.

Regarding the ABCC subfamily, ABCC2 (MRP2) was recently found to be involved in cisplatin resistance of melanoma. In fact, cisplatin resistant cells overexpressed mRNA of ABCC2, reducing the formation of platinum-induced intra-strand cross-links in the nuclear DNA [32]. This decrease in DNA platination was accompanied by an accelerated reentry into the cell cycle after the typical cisplatin induced G2 arrest and a resistance to undergo apoptosis [32]. An Overview of the Apoptotic Process

Fig. (2). Chemical structures of methotrexate and SN-38, both transported by ABCG2.

In principle, there are two alternative pathways that initiate apoptosis: one is mediated by death receptors on the cell surface- extrinsic pathway and the other is mediated by mitochondria-intrinsic pathway [33-35] (Fig. 4). Death receptors are members of the tumor-necrosis factor (TNF) receptor superfamily and comprise a subfamily that is characterized by an intracellular domain- the death domain [34, 35]. Binding of the ligands to their receptors was believed to cause aggregation (trimerization) of the receptors and clustering of death domain in the cytoplasmic region of the receptors. This, in turn, was thought to lead to the downstream

Drug Resistance in Melanoma: New Perspectives

Current Medicinal Chemistry, 2007, Vol. 14, No. 3

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Fig. (4). There are two major apoptotic pathways in mammalian cells, as shown in this figure. The extrinsic pathway, also known as the death receptor pathway, is triggered by specific ‘death ligands’ such as CD95 and tumor necrosis factor (TNF) receptor 1. CD95 ligand binds to the receptor causing them to cluster and form the death inducing signaling complex, which recruits multiple procaspase-8 molecules via the adaptor molecule FADD (Fas-associated death domain protein). This results in caspase-8 activation. Further activation of other caspases like caspase-3 initiates apoptosis. The Internal Signal Pathway is also known as the mitochondrial pathway, which is driven by the inactivation of bcl-2. DNA damage, which is un-reparable via DNA repair mechanisms and activates this pathway. Activation of a pro-apoptotic Bcl2 family member, which is attached to intracellular membranes, either via proteolysis or de-phosphorylation affects the mitochondria. Bax, Bad, Bim and Bid can shuttle between organelles within the cell causing activation of this pathway. Both pro- and anti-apoptotic Bcl-2 members regulate cytochrome c exit, which associates with Apaf 1 and causes pro-caspase 9 to form an apoptosome. This then activates caspase 3 to induce the apoptotic programme that branches into other sub-programmes, which cumulatively cause apoptosis.

signaling cascade that causes programmed cell death. This view has been challenged by studies on FAS, which indicate that FAS is assembled as trimers in the cell membrane even in the absence of FASL and that trimerization is a prerequisite for signaling by FASL [36]. Apoptosis seems to depend on a change of the anti-apoptotic Bcl2 family protein BID by caspases [37]. DNA damage activates mitochondria intrinsic pathway. Bcl-2 family member affects mitochondria. Both pro- and anti-apoptotic Bcl-2 members regulate cyt-c and associate with Apaf-1,causing pro-caspase 9 apoptosome. This then activates caspase 3 to induce the apoptotic programme that branches into other sub-programmes, which cumulatively cause apoptosis. Melanoma, Apoptosis and Chemoresistance Acquired resistance to mechanisms of programmed cell death is one of the hallmarks of cancer. One of the common mechanisms underlying the resistance of melanoma to phar-

macological therapies is the development of defects in the cell death pathways. There are two distinct pathways to cell death apoptotic and non-apoptotic. The role of non-apoptotic pathway in controlling melanoma response to therapy remains to be elucidated further. Regarding the apoptotic pathway, apoptosis proteaseactivating factor-1 (Apaf-1) a key regulator of mitochondrial apoptotic pathway, was demonstrated to be deeply involved in melanoma progression and chemoresistance. Apaf-1 is a down-stream effector of p53 in DNA damage-induced apoptosis [38, 39]. However, melanomas display a very low rate of p53 mutations despite their extreme chemoresistance [40, 41]. Few studies have investigated the expression of Apaf-1 in human melanoma. Soengas et al. were the first to demonstrate that Apaf-1 protein and mRNA expression are frequently down regulated in metastatic melanoma cell lines and tumor specimens [42]. Moreover, they have demonstrated that the frequency of Apaf-1 loss of heterozygosity

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(LOH) is significantly lower in primary melanomas than in metastatic melanoma, thus, the loss of Apaf-1 could be a more significant factor for progression than initiation of melanoma. Interestingly, Apaf-1 protein levels can be restored by the addition of the methylation inhibitor 5-azadeoxycytidine or the histone deacetylase inhibitor tricostatin A [43]. This result indicated that Apaf-1 is a target gene for methylation during the development of malignant melanoma. Whether methylation blocks Apaf-1 mRNA expression directly by interfering with the recruitment of transcription factors at the Apaf-1 promoter or by affecting a regulator of Apaf-1 expression remains an open question [44]. Lower Apaf-1 expression was found in melanomas developed to metastasis in comparison to melanocytes [42-48]. Many molecular changes have the potential to cause apoptotic dysregulation, including activation of antiapoptotic factors, inactivation of pro-apoptotic effectors, and/or reinforcement of survival signals [49] (Fig. 4). Overexpression of apoptotic inhibitors such as survivin and FLIP (FLICE-inhibitory protein) have been reported in malignant melanoma [50, 51] as well as after TSA or SAHA treatments [52]. Unlike many other human cancers, melanomas rarely harbor p53 mutations [53, 54]. Therefore, other components of the p53 pathway, either upstream or down stream of p53 are likely defective in melanoma and one such candidate is the pro-apoptotic gene, PUMA (p53 upregulated modulator of apoptosis). Recently, its expression was demonstrated to be significantly reduced in human cutaneous melanomas [55], suggesting that it may be an important prognostic marker for human melanoma. One of the key regulators of apoptosis belongs to a family of proteins known as inhibitor of apoptosis (IAP), characterized by the presence of one or more conserved baculovirus IAP repeat (BIR) domains [56, 57] (Fig. 4). To date, eight members of the IAP family have been identified. The antiapoptotic function of certain members has been attributed to direct binding and inhibition of caspases [58-64]. Of the known IAP, X-linked inhibitor of apoptosis (XIAP) protein is the best characterized and the most potent inhibitor of apoptosis. The anti-apoptotic activity of XIAP is negatively regulated by two mitochondrial proteins: Smac/DIABLO and HtrA2/Omi. Both proteins are released to the cytosol along cytochrome c during mitochondrial destabilization in response to apoptotic stimuli. Proteolytic cleavage of mitochondrial targeting sequence generates an amino terminal tetrapeptide, which is crucial for Smac/DIABLO and Htr2/Omi to interact and inhibit XIAP by sterically preventing the XIAP-caspase interaction [65, 66]. Recently, a novel XIAP binding protein termed XIAP-associated factor 1 (XAF1) has been identified using two hybrid system [67]. XAF1 was demonstrated to reverse the anti-apoptotic effect of XIAP in response to anti-apoptotic stimuli triggered by serum withdrawal and etoposide treatment [68]. Furthermore, a recent paper showed that XAF1 expression is significantly reduced in human melanoma [69]. STEM CELLS AND MULTI-DRUG RESISTANCE The cancer stem cells hypothesis opens new perspectives for the treatment of tumors. However, many efforts need to be done in order to understand better the biology of these cells in comparison to normal stem cells. By their nature,

Caterina A.M. La Porta

cancer stem cells appear biologically distinct from other cancer cell types. Moreover, certain natural properties of these cells are likely to increase their resistance to standard chemotherapy agents. Thus, if cancer therapies do not effectively target the cancer stem cell population during initial treatment, then relapse may occur as a consequence of cancer stem cell-driven tumor expansion. Therefore, in developing new cancer therapeutics, the toxicity toward tumor stem cells is an important priority. Interestingly, recent evidences demonstrate how certain mutations might confer embryonic or undifferentiated features to malignant cells, enabling them to show stem-cell like behaviors such as self-renewal and extensive proliferation [70, 71]. On the population level, different malignancies may appear to be heterogeneous with respect to drug responsiveness. Cancer that responds to therapy initially may appear to acquire drug resistance during the course of treatment. Other forms of cancer may appear to be intrinsically resistant. The cancer stem cell hypothesis posits that in both the cancer initiating cells and its source of replenishment under selective pressure has innate drug resistance by virtue of its resting stem cell phenotype. Acquired drug resistance in more differentiated cancer cells through gene amplification or rearrangement may contribute to an aggressive phenotype. One of the defining characteristics of adult tissue stem cells is their constitutive resistance to environmental toxin, including most chemotherapeutics agents. The constitutive drug resistance of normal tissue stem cells is mediated by MDR transporters and detoxifying enzymes. DNA repair mechanism; tolerance to damage and telomerase activity also contribute to the stability of normal tissue stem cells. The cancer stem cell expresses constitutive MDR activity, which is independent of drug exposure and is down regulated in more differentiated tumor progeny. It has been proposed that selective pressure imposed by chemotherapy leads to both mutation and secondary genetic changes, including MDR up regulation in the tumor bulk. However, the major barrier to the therapy is the quiescent tumor stem cell with constitutive MDR (see more details in the recent review) [72]. The use of PCG complexes, which play a pivotal role in the self-renewal of stem cells or Bmi1 and SU(Z)12 factors, which are downstream of Sonic hedgehog (Shh) and Wnt signaling, respectively, might provide new therapeutic strategy in order to act directly on cancer stem cells (see more details in the recent review) [73]. Therefore, since a stem cell population exists in melanoma [74], there is the hope to develop new strategies in melanoma treatments in the next years, using the cancer stem cells as the target instead of tumor cells. Accordingly, it looks urgent to study the biology of melanoma cancer stem cells in comparison to tumor cells. REFERENCES [1] [2] [3] [4] [5]

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Drug Resistance in Melanoma: New Perspectives

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