有研究者发现，一种名为cysmethynil的化合物在小鼠中不仅能抑制前列腺肿瘤的生长，还能使某些癌细胞自杀。此外，与其它常规治疗方法相比，cysmethynil能作用于特殊的细胞死亡通路，这意味着它能有效地与其他药物联合使用。相关论文发表在《生物化学杂志》（JBC）上。
Cysmethynil的靶标是异戊烯半胱氨酸羧甲基转移酶（isoprenylcysteine carboxyl-methyltransferase，Icmt），这种酶参与对很多蛋白质来说都很重要的生化反应，其中包括RAS蛋白质家族，它们是导致癌症发生的一种重要因素。
Patrick Casey及其同事们曾经鉴定出cysmethynil是一种潜在的癌细胞抑制剂。为了研究这种药物能否在动物体中发挥作用，他们利用小鼠进行检测，在小鼠中植入人的前列腺肿瘤细胞，发现这种药物能显著缩小肿瘤的体积，并且没有任何毒副作用。
进一步的研究显示，cysmethynil能诱导癌细胞进入一种生长停滞状态，并且往往能触发细胞凋亡程序。有趣的是，尽管cysmethynil不能激活常规的细胞死亡通路——细胞凋亡，但是它能开启自噬，该过程使癌细胞从内部逐渐吞食自身。
Casey及其同事们指出，由于其特殊的作用模式，cysmethynil可以作为其他药物疗法很好的补充，还可能在治疗抗凋亡类型的癌症中发挥作用。
原始出处：
JBC，Vol. 283, Issue 27, 18678-18684，Mei Wang，Patrick J. Casey
A Small Molecule Inhibitor of Isoprenylcysteine Carboxymethyltransferase Induces Autophagic Cell Death in PC3 Prostate Cancer Cells*
Mei Wang, Wanloo Tan, Jin Zhou, Jolene Leow, Meilin Go, How Sung Lee?, and Patrick J. Casey1
From the Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore 169547, the Department of Pharmacy, National University of Singapore, Singapore 117543, and the ?Department of Pharmacology, National University of Singapore, Singapore 117597
A number of proteins involved in cell growth control, including members of the Ras family of GTPases, are modified at their C terminus by a three-step posttranslational process termed prenylation. The enzyme isoprenylcysteine carboxylmethyl-transferase (Icmt) catalyzes the last step in this process, and genetic and pharmacological suppression of Icmt activity significantly impacts on cell growth and oncogenesis. Screening of a diverse chemical library led to the identification of a specific small molecule inhibitor of Icmt, cysmethynil, that inhibited growth factor signaling and tumorigenesis in an in vitro cancer cell model (Winter-Vann, A. M., Baron, R. A., Wong, W., dela Cruz, J., York, J. D., Gooden, D. M., Bergo, M. O., Young, S. G., Toone, E. J., and Casey, P. J. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 4336–4341). To further evaluate the mechanisms through which this Icmt inhibitor impacts on cancer cells, we developed both in vitro and in vivo models utilizing PC3 prostate cancer cells. Treatment of these cells with cysmethynil resulted in both an accumulation of cells in the G1 phase and cell death. Treatment of mice harboring PC3 cell-derived xenograft tumors with cysmethynil resulted in markedly reduced tumor size. Analysis of cell death pathways unexpectedly showed minimal impact of cysmethynil treatment on apoptosis; rather, drug treatment significantly enhanced autophagy and autophagic cell death. Cysmethynil-treated cells displayed reduced mammalian target of rapamycin (mTOR) signaling, providing a potential mechanism for the excessive autophagy as well as G1 cell cycle arrest observed. These results identify a novel mechanism for the antitumor activity of Icmt inhibition. Further, the dual effects of cell death and cell cycle arrest by cysmethynil treatment strengthen the rationale for targeting Icmt in cancer chemotherapy.
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