Melanoma: Ma Y

Ma Y, Kurtyka CA, Boyapalle S, Sung SS, Lawrence H, Guida W, Cress WD. · Molecular Oncology Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA. · Cancer Res. · Pubmed #18676853 links to  free full text

Abstract: HLM006474 was identified using a computer-based virtual screen and the known crystal structure of the DNA-bound E2F4/DP2 heterodimer. Treatment of multiple cell lines with HLM006474 resulted in the loss of intracellular E2F4 DNA-binding activity as measured by electrophoretic mobility shift assay within hours. Overnight exposure to HLM006474 resulted in down-regulation of total E2F4 protein as well as known E2F targets. The effects of HLM006474 treatment on different cell lines varied but included a reduction in cell proliferation and an increase in apoptosis. HLM006474 induced apoptosis in a manner distinct from cisplatin and doxorubicin. E2F4-null mouse embryonic fibroblasts were less sensitive than wild-type counterparts to the apoptosis-inducing activity of the compound, revealing its biological specificity. A375 cells were extremely sensitive to the apoptosis-inducing activity of the compound in two-dimensional culture, and HLM006474 was a potent inhibitor of melanocytes proliferation and subsequent invasion in a three-dimensional tissue culture model system. Together, these results suggest that interference with E2F activity using small molecules may have clinical application in cancer therapy.

Wang J, Xie S, Li Y, Guo Y, Ma Y, Zhao J, Phanstiel O, Wang C. · Institute of Natural Products & Medicinal Chemistry, Henan University, Henan, Kaifeng 475001, China. · Bioorg Med Chem. · Pubmed #18539036 No free full text.

Abstract: A series of unsymmetrically substituted polyamine derivatives were prepared and their cytotoxicities in mouse leukemia L1210, melanoma B16, and HeLa cells were investigated. The in vitro cytotoxicity revealed that these conjugates could recognize the polyamine transporter, and the N-ethyl modified homospermidine moiety may be another efficient carrier as homospermidine even though the introduction of terminal alkyl groups led to reduced cytotoxicity in comparison with the un-substituted counterpart 1. The ornithine decarboxylase and topoisomerase II inhibition experiments indicated that ODC and TOPO II were potential, but not unique targets of these conjugates. Furthermore, the in vivo antitumor activities illustrated that the representative conjugate 2f and the homospermidine analogue 1 evidently inhibited the tumor growth and significantly increased the survival time of mice-bearing sarcoma 180 cells.

Yang B, O'Herrin SM, Wu J, Reagan-Shaw S, Ma Y, Bhat KM, Gravekamp C, Setaluri V, Peters N, Hoffmann FM, Peng H, Ivanov AV, Simpson AJ, Longley BJ. · Department of Dermatology and Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin Medical School, Madison, Wisconsin 53706, USA. · Cancer Res. · Pubmed #17942928 links to  free full text

Abstract: 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, p53wt/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.

Xie S, Cheng P, Liu G, Ma Y, Zhao J, Chehtane M, Khaled AR, Phanstiel O, Wang C. · Institute of Natural Products & Medicinal Chemistry, Henan University, Henan, Kaifeng 475001, China. · Bioorg Med Chem Lett. · Pubmed #17574415 No free full text.

Abstract: N1-(Arylalkyl)homospermidines (1c-1f) and terminally piperazine-substituted homospermidine conjugates (2a-2e) were synthesized and evaluated for cytotoxicity in mouse leukemia L1210, alpha-difluoromethylornithine (DFMO)-treated L1210, melanoma B16, spermidine (SPD)-treated B16, and HeLa cell lines. Results demonstrated that homospermidine was a more effective vector than piperazine-substituted homospermidine in ferrying diverse arenes into cells via the polyamine transporter. The leading compound, 9-anthracenemethyl-homospermidine (1a), was shown to induce apoptosis in B16 cells and IL-3 dependent FL5.12A pro-B cells. The novel conjugate 4-biphenylmethyl-homospermidine (1e) could also induce apoptosis. However, it exhibited different effect on the cell cycle of B16 cells compared to 1a.

Chandrasoma S, Moatamed N, Chang A, Daneshmand S, Ma Y. · Department of Urology, University of Southern California, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. · Appl Immunohistochem Mol Morphol. · Pubmed #15551744 No free full text.

Abstract: We report 3 recent cases of angiomyolipoma of the kidney. Although generally regarded as a benign neoplasm, angiomyolipoma rarely behaves in an aggressive manner, producing complicated clinical courses leading to metastasis and death. The presence of epithelioid elements within the tumor can result in difficulty differentiating benign from malignant angiomyolipoma and differentiating this tumor from renal adenocarcinoma. The presence of lymph node involvement can cause difficulty in differentiating multicentric disease in lymph nodes from metastasis to lymph nodes. The presence of cytologic abnormalities in the primary tumor can result in difficulty in differentiating atypia in benign angiomyolipoma from malignant sarcomatous transformation of a benign lesion. The 3 cases reported show many of these problems. Criteria for predicting malignancy in epithelioid tumors and sarcomatous transformation are not well recognized because of the rarity of this entity. The typical immunophenotype of all types of angiomyolipoma (cytokeratin-negative and melanomarkers-positive) is very useful in diagnosis but does not help in the differentiation from renal adenocarcinoma at frozen section. We report the empiric use of Ki67 and p53 in these cases as adjuncts to clinical and histologic assessment in predicting behavior. High Ki67 expression was a feature of malignant epithelioid angiomyolipoma. Low levels of p53 expression were seen in the angiomyolipoma with sarcomatous transformation. Benign angiomyolipomas were consistently negative for both Ki67 and p53.

Yang R, Yang X, Zhang Z, Zhang Y, Wang S, Cai Z, Jia Y, Ma Y, Zheng C, Lu Y, Roden R, Chen Y. · Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Gene Ther. · Pubmed #16838032 No free full text.

Abstract: Antigen-presenting cells such as dendritic cells (DCs) play a critical role in inducing and regulating immune responses. One effective strategy for DC-based immunotherapy is to regulate maturation and function of DC. In this study, we apply single-walled carbon nanotubes (SWNTs) to carry small interfering RNA (siRNA) to reach, enter and genetically modify DCs in vivo. We prepared positively charged SWNTs (SWNTs+) using 1,6-diaminohexane which was demonstrated by transmission electron microscopy equipped with energy-dispersive X-ray spectroscopy and atomic force microscope. The functionalized SWNTs+ could absorb siRNA to form complexes of siRNA with SWNTs. These siRNA:SWNT+ complexes were preferentially taken up by splenic CD11c+ DCs, CD11b+ cells and also Gr-1+CD11b+ cells comprising DCs, macrophages and other myeloid cells to silence the targeting gene. Suppressor of cytokine signaling 1 (SOCS1) restricts the ability of DCs to break self-tolerance and induce antitumor immunity. Infusion of SWNTs+ carrying SOCS1siRNA reduced SOCS1 expression and retarded the growth of established B16 tumor in mice, indicating the possibility of in vivo immunotherapeutics using SWNTs-based siRNA transfer system.