The MAGE-A, MAGE-B, and MAGE-C protein families comprise the class-I MAGE/cancer testes antigens, a group of highly homologous proteins whose expression is suppressed in all normal tissues except developing sperm. Aberrant expression of class I MAGE proteins occurs in melanomas and many other malignancies, and MAGE proteins have long been recognized as tumor-specific targets; however, their functions have largely been unknown. Here, we show that suppression of class I MAGE proteins induces apoptosis in the Hs-294T, A375, and S91 MAGE-positive melanoma cell lines and that members of all three families of MAGE class I proteins form complexes with KAP1, a scaffolding protein that is known as a corepressor of p53 expression and function. In addition to inducing apoptosis, MAGE suppression decreases KAP1 complexing with p53, increases immunoreactive and acetylated p53, and activates a p53 responsive reporter gene. Suppression of class I MAGE proteins also induces apoptosis in MAGE-A–positive, p53^wt/wt parental HCT 116 colon cancer cells but not in a MAGE-A–positive HCT 116 p53^−/− variant, indicating that MAGE suppression of apoptosis requires p53. Finally, treatment with MAGE-specific small interfering RNA suppresses S91 melanoma growth in vivo, in syngenic DBA2 mice. Thus, class I MAGE protein expression may suppress apoptosis by suppressing p53 and may actively contribute to the development of malignancies and by promoting tumor survival. Because the expression of class I MAGE proteins is limited in normal tissues, inhibition of MAGE antigen expression or function represents a novel and specific treatment for melanoma and diverse malignancies. [Cancer Res 2007;67(20):9954–62]

According to the World Cancer Report , skin cancer constitutes ∼30% of all newly diagnosed cancers in the world, and solar ultraviolet (UV) radiation (particularly, its UVB component; 290–320 nm) is an established cause of ∼90% of skin cancers. The available options have proven to be inadequate for the management of skin cancers. Therefore, there is an urgent need to develop mechanism‐based novel approaches for prevention/therapy of skin cancer. In this study, we evaluated the chemopreventive effects of resveratrol against UVB radiation‐mediated skin tumorigenesis in the SKH‐1 hairless mouse model. For our studies, we used a UVB initiation‐promotion protocol in which the control mice were subjected to chronic UVB exposure (180 mJ/cm ² , twice weekly, for 28 weeks). The experimental animals received either a pretreatment (30 min before each UVB) or post‐treatment (5 min after UVB) of resveratrol (25 or 50 micro mole/0.2 ml acetone/mouse). The mice were followed for skin tumorigenesis and were killed at 24 h after the last UVB exposure, for further studies. The topical application of skin with resveratrol (both pre‐ and post‐ treatment) resulted in a highly significant 1 ) inhibition in tumor incidence, and 2 ) delay in the onset of tumorigenesis. Interestingly, the post‐treatment of resveratrol was found to impart equal protection than the pretreatment; suggesting that resveratrol‐mediated responses may not be sunscreen effects. Because Survivin is a critical regulator of survival/death of cells, and its overexpression has been implicated in several cancers, we evaluated its involvement in chemoprevention of UVB‐mediated skin carcinogenesis by resveratrol. Our data demonstrated a significant 1 ) up‐regulation of Survivin (both at protein‐and mRNA‐ levels), 2 ) up‐regulation of phospho‐Survivin protein, and 3 ) down‐regulation of proapoptotic Smac/DIABLO protein in skin tumors; whereas treatment with resveratrol resulted in the attenuation of these responses. Our study also suggests that resveratrol enhanced apoptosis in UVB‐exposure‐mediated skin tumors. Our study, for the first time, demonstrated that 1 ) resveratrol imparts strong chemopreventive effects against UVB exposure‐mediated skin carcinogenesis (relevant to human skin cancers), and 2 ) the chemopreventive effects of resveratrol may, at least in part, be mediated via modulations in Survivin and other associated events. On the basis of our work, it is conceivable to design resveratrol‐containing emollient or patch, as well as sunscreen and skin‐care products for prevention of skin cancer and other conditions, which are believed to be caused by UV radiation.

Cutaneous T-cell lymphoma (CTCL) is a hematologic malignant disease whose most common variant, mycosis fungoides, is characterized by flat cutaneous patches that become progressively infiltrated to form plaques and tumors.¹ Extracutaneous tissues can become involved in the later stages of disease. Sézary syndrome is the term given to the leukemic variant of CTCL when accompanied by erythroderma. Considerable evidence suggests that early CTCL has apoptotic defects that render it more of a lymphoaccumulative disorder than a lymphoproliferative disorder.^2-10 This includes a low apoptotic rate, low proliferative rate, relatively indolent clinical course, and no enhanced survival following conventional chemotherapy.

This article reviews methotrexate and the more potent, related compound, pralatrexate, for the treatment of cutaneous T-cell lymphomas, including mycosis fungoides, Sézary syndrome, and CD30+ lymphoproliferative disorders. Although these folate antagonists are traditionally viewed as antiproliferative cell cycle inhibitors, it is recognized that they inhibit DNA methylation, providing a rationale for their use as epigenetic regulators and cell proliferation inhibitors. The underlying mechanisms are outlined, key supporting data presented, followed by brief mention of recent mathematical modeling supporting the general superiority of combination therapy. Several novel examples involving folate antagonists are proposed.