Sphingosine kinase inhibition: a potential new anticancer strategy

Scientists from Penn State College of Medicine in Hershey, Pennsylvania have identified several nonlipid inhibitors of human sphingosine kinase (SK).

Mounting evidence indicates that SK plays a “pivotal” role in regulating tumor proliferation and can act as an oncogene, Dr. Charles D. Smith and colleagues note in the September 15th issue of the journal Cancer Research.”A few lipid-based inhibitors of SK have been previously described, but in this paper we show several new ‘drug-like’ compounds that inhibit the kinase and that are cytotoxic toward tumor cells both in vitro and in vivo,” Dr. Smith told Reuters Health.To further assess SK’s involvement in human tumors, they analyzed levels of SK RNA in paired samples of cDNA prepared from tumors and normal adjacent tissue. Expression of SK was two-fold higher in tumors of the breast, colon, lung, ovary, stomach, uterus, kidney, and rectum compared with normal tissue.This study “provides the first indication” that SK may be commonly overexpressed in a variety of solid tumors, the researchers say. Inhibiting SK, therefore, maybe an effective therapy for cancer and other hyperproliferative diseases.On that front, Dr. Smith’s group screened a library of synthetic compounds, identifying a number of structurally novel selective inhibitors of human SK.Several of these compounds showed anti-tumor activity against a panel of tumor cell lines, including multi-drug resistant cell lines, and induced tumor cell apoptosis at sub- to micromolar concentrations, “making them more potent than any other reported SK inhibitor.”Moreover, in tumor-bearing mice, a “prototypical” SK inhibitor showed moderate antitumor activity in the absence of overt toxicity.”We will be presenting some follow-up data on the in vivo activity of these compounds at the AACR-NCI-EORTC meeting in Boston in November,” Dr. Smith told Reuters Health. “We are also currently optimizing these compounds for clinical testing.”The researcher expects to have candidate SK inhibitors ready for clinical trials in the next couple of years.(Source: Cancer Res 2003;63:000-000: Reuters Health: Megan Rauscher: October 8, 2003: Oncolink)