Tumor cells destroyed by inhibiting 2 key kinases in Mice

In a study published in the recent issue of Cancer Research, Pennsylvania medical researchers state that tumors in which chemotherapy is unsuccessful can be targeted with cancer therapy that restricts the activity of 2 enzymes in mouse tumor cells.

Wafik S. El-Deiry, M.D. Ph.D., American Cancer Society Research Professor, Rose Dunlap Professor and chief of hematology/oncology, Penn State College of Medicine said that “We’ve known for well over a decade that when tumors become hypoxic they become resistant to chemotherapy and radiotherapy. This is a huge problem in the treatment of patients with cancer. As tumors progress, they have regions that are not well perfused with blood vessels and tumors become hypoxic.”

An oxygen- deficient hypoxic tumor has insufficient numbers of tumor RBCs with the blood vessels to facilitate oxygen transport all through the tumor.

According to El-Deiry and his team, the drug sangivamycin-like molecule 3 (SLM3) prevented the multiplication of tumor cells in lab mice by inhibiting two kinases, or enzymes: GSK-3ß (involved in cell growth and death regulation), and CDK1 (involved in cell division and blood vessel growth regulation). Thus, SLM3-treated tumor cells are rendered more susceptible to chemotherapy and destroyed.

Associate director for translational research, Cancer Institute, El-Deiry said, “If you just inhibit GSK-3ß, that may not be enough and not necessarily desirable. But there’s something fortuitous about the dual targeting of these two kinases, (GSK-3ß and CDK-1), with respect to cancer therapy. If you inhibit these two kinases, the dual inhibition works together to kill hypoxic tumor cells.”

He added, “While pure inhibition of GSK-3ß can promote cell proliferation, the combination of GSK-3ß and CDK-1 inhibition not only inhibits cell proliferation but also promotes cell death.”

In an effort to locate SLM3, researchers reviewed a chemical library to select molecules that induce apoptosis in hypoxic tumor cells. They identified SLM3, and additionally found eight other structurally similar molecules.
SLM3 was that version of the apoptosis-inducing molecule that worked along with TRAIL, which is a naturally occurring molecule in the body that determines the time of cell death. It activates the process of targeting and shutting down tumor cells to prevent them from spreading.

A nucleoside analog SLM3 inhibits the multiplication of tumor cells by preventing cells from DNA duplication. Molecules like ATP (energy source for the body) and nucleic acids are derived from the building blocks called nucleosides. ATP competes with a nucleoside analog to restrict the activity of kinases such as CDK1 and GSK-3ß1.

While CDK1 limits the ability of the tumor to multiply and produce more blood vessels, GSK-3ß is involved in the regulation of cell growth and death. SLM3 inhibits both these kinases.

El-Deiry said, “The bottom line is the molecules actually work to shrink tumors when these molecules are combined with chemo or TRAIL therapy. We think that these are important observations that need to be tested further in the clinic.”
Nathan G. Dolloff, assistant professor of hematology/oncology; Joshua E. Allen, graduate student, hematology/oncology; Yingqiu Y. Liu, research specialist; and David T. Dicker, technical specialist, were amongst the other researchers from Penn State College of Medicine. Additionally, Patrick A. Mayes, former graduate student, now at GlaxoSmithKline; Colin J. Daniel, graduate student, and Rosalie C. Sears, associate professor, molecular and medical genetics, Oregon Health Science University; J. Judy Liu and David I. H. Jee, graduate students, Harvard University; Lori S. Hart, research associate, and Jay F. Dorsey, assistant professor, radiation oncology, Emma E. Furth, professor of pathology and laboratory medicine and Peter S. Klein, associate professor of hematology/oncology, University of Pennsylvania; Kageaki Kuribayashi, Sapporo Medical University, Japan; and J. Martin Brown, professor of radiation oncology, Stanford University, were working on this research.

This research was supported by grants from the National Institutes of Health.