Research Interests

Inhibition of eicosanoid synthesis as means to decrease tumor growth and tumor angiogenesis

Eicosanoids are oxygenated derivatives of polyunsaturated fatty acids with 20 carbons, mainly arachidonic acid (20:4, -6) and eicosapentaenoic acid (20:5, -3). The majority of them are enzymatically synthesized in essentially all mammalian cells. The specific types of synthesized eicosanoids depends on the specific cell/tissue. The biological activities of the different eicosanoids are diverse and depend on the tissue/cell affected and the endocrinological, physiological or pathophysiological state of the animal. On the physiological level several eicosanoids work in an autocrine/paracrine fashion to contract (prostanoids PGE2, PGF2 , TXB2) or dilate (PGI2) peripheral blood vessels. Eicosanoids formed in specific leukocytes are involved in inducing and propagating the immune/ inflammatory response mounted against invading foreign cells. Mechanistically, eicosanoids often act via interaction with outer membrane receptors that regulate adenilyl cyclase activity to modulate intracellular cAMP levels. Two basic observations link prostanoids and cancer. The first is the increased expression and activity of the prostanoids-producing enzyme cyclooxygenase-2 (COX-2) and the resulting generation of PGE2, in human tumors and in experimental tumors in rodents. The second is a large body of epidemiological and clinical data that documents a significant attenuation of tumor incidence in men and tumor growth in rodents and men by treatment with non-steroidal anti-inflammatory drugs (abbrev. NSAIDs, e.g. aspirin, ibuprofen) that inhibit the activity of the cyclooxygenase enzymes. Over the last decade, a considerable amount of data obtained from studies with tumor cells grown in culture has provided important clues as to the mechanisms of action of NSAIDs on cellular signaling which translates into enhanced apoptosis and cell death. However, these data are sometimes of limited value since they were obtained in in vitro studies using non-physiologically high NSAIDs concentrations.

The research in our lab focuses on in vivo studies in mice, discovering and investigating cellular signaling mechanisms that are regulated by NSAIDs and other eicosanoids inhibitors. A key element in these studies is to determine whether or not these effects are due to the eicosanoid inhibiting properties of the specific drug or agent. The specific projects currently being investigated include:

1. Characterization of the effects of chiral (asymmetric) NSAIDs (COX-inhibiting S-NSAID vs. non-inhibiting R-NSAID) on tumor growth and cell cycle parameters in vivo.
2. Characterization of the anti-tumorigenic mechanisms of action of NSAIDs that do not inhibit either of the COX enzymes. Emphasis is on searching for novel non-COX mechanisms that nevertheless lead to attenuation of prostanoids formation.
3. Demonstration of an unequivocal anti-carcinogenic action of lipoxygenase inhibitors in vivo and characterization of the molecular/cellular basis for this effect.
4. Evaluation of in vivo inhibitors of inducible Nitric Oxide Synthase (NOS) as adjunctive cancer therapy agents for use in conjunction with COX inhibitors. 5. Evaluation in vivo of the cholesterol-lowering, HMG-CoA Reductase inhibitors (Lovastatin and other statins) as adjunctive cancer therapy agents for use together with COX inhibitors.

A second branch of our research effort focuses on dietary remodeling of cellular fatty acids in such a way as to substantially reduce arachidonic acid content and increase the content of long chain -3 fatty acids EPA and DHA. We (and others) have shown that such a change leads to a significant attenuation of tumor growth in experimental models in rodents. In full agreement with this, data from recent human epidemiological studies showed an inverse relationship between consumption of fish or fish oil (rich source of the w-3 fatty acids) and the prevalence of prostate cancer in men and breast cancer in women.

The studies focus on:
Determining the cellular effects seen in tumors grown in vivo, following dietary "w-3 for w-6" remodeling in mice. Testing combinations of both NSAID and dietary w-3 fatty acids to see whether such a paradigm will enhance the anti-tumorigenic potency and efficacy of conventional chemotherapy or radiotherapy protocols, especially in highly resistant, mdr positive, tumor types.

Selected Publications

1. Levin, G., Kariv, N., Khomiak, E. and Raz, A. (2000) Indomethacin inhibits the accumulation of tumor cells in mouse lungs and subsequent growth of lung metastases. Chemotherapy 46: 429-437.
2. Yaniv, E., Przedecki, F., Levin, G., Kariv, N. and Raz, A.(2001) Comparative effects of indomethacin on cell proliferation and cell cycle progression in tumor
   cells grown in vitro and in vivo. Biochem. Pharmacol. 61: 565-571
3. Raz, A. (2002) Is inhibition of cyclooxygenase required for the anti-tumorigenic effects of anti-inflammatory drugs (NSAIDs)? In vitro versus in vivo results and the relevance for the prevention of cancer. Biochem. Pharmacol. 63: 343-347.
4. Levin, G., Duffin, K.L., Obukowicz, M.G., Hummert, S.L., Fujiwara, H., Needleman, P. and Raz, A. (2002) Differential metabolism of dihomo--linolenic acid and arachidonic acid by COX-1 and COX-2: Implication for cellular synthesis of PGE1 and PGE2. Biochemical Journal 365: 489-496.