Abstract
A novel anti-tumour amphibian oocyte RNase, ONCONASER (ONC), previously known as P-30 Protein, is in the clinical trials. The effect of ONC alone and in combination with lovastatin (LVT), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme of mevalonate (MVA) and cholesterol synthesis pathway, in three human tumour cell lines ASPC-1 pancreatic, A-549 lung, and HT-520 lung carcinomas, has been presently studied. A synergism between ONC and LVT in inducing the cytostatic and cytotoxic effects was observed. The cytostatic effect, seen during the early phase of the treatment with this combination of drugs was manifested as prolongation of the cell cycle duration, especially of the G1 phase; cell death was apparent after 72 h of treatment. The synergistic effect of ONC and LVT was also evident in the clonogenicity assays. Both LVT lactone and its in vitro activated beta-hydroxy acid form, alone and in respective combinations with ONC, exerted similar degree of growth suppression. The effects of both forms of LVT (used alone or in combination with ONC) were reversed by MVA, which suggests that HMG-CoA reductase inhibition is a primary mechanism of LVT action. The data indicate that the LVT lactone can be activated intracellularly by tumour cells studied, and that the combination of ONC with LVT can produce significantly enhanced anti-tumour activities.
Highlights
Guanosine triphosphate (GTP)-binding proteins (Gproteins), whether heterotrimeric or monomeric such as products of ras, rho, R-ras, or rab genes (Gilman, 1987; Finegold et al, 1990), all require to be anchored via farnesylated carboxyl-terminal cysteine to the inner surface of the plasma membrane, in order to be active in signal transduction pathways (Finegold et al, 1990; Barbacid, 1987; Madaule & Axel, 1985; Chardin & Tavitian, 1986; Lowe et al, 1987; Touchot et al, 1987; Neer & Clapham, 1988; Schafer et al, 1989)
The farnesylation process is inhibited by LVT (Repko & Maltese, 1989), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase
The ASPC-1 pancreatic and A-549 lung adenocarcinoma cell lines were obtained from the American Type Culture Collection and were cultured as described previously (Mikulski et al, 1990b)
Summary
Guanosine triphosphate (GTP)-binding proteins (Gproteins), whether heterotrimeric or monomeric such as products of ras, rho, R-ras, or rab genes (Gilman, 1987; Finegold et al, 1990), all require to be anchored via farnesylated carboxyl-terminal cysteine to the inner surface of the plasma membrane, in order to be active in signal transduction pathways (Finegold et al, 1990; Barbacid, 1987; Madaule & Axel, 1985; Chardin & Tavitian, 1986; Lowe et al, 1987; Touchot et al, 1987; Neer & Clapham, 1988; Schafer et al, 1989). It was observed that LVT suppresses cell proliferation by arresting cells in GI phase of the cell cycle (Jakobisiak et al, 1991). It is likely, that the anti-proliferative effect of LVT is the consequence of the impairment of the signal transduction by this drug. Similar inhibition of cell proliferation has been previously observed with other HMG-CoA reductase inhibitors (QuesneyHuneeus et al, 1979; Sinensky & Logel, 1985; Doyle & Kandutsch, 1988)
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