Abstract
Plant metabolites are valuable sources of novel therapeutic compounds. In an anti-telomerase screening study of plant secondary metabolites, the aporphine alkaloid boldine (1,10-dimethoxy-2,9-dihydroxyaporphine) exhibited a dose and time dependent cytotoxicity against hepatocarcinoma HepG-2 cells. Here we focus on the modes and mechanisms of the growth-limiting effects of this compound. Telomerase activity and expression level of some related genes were estimated by real-time PCR. Modes of cell death also were examined by microscopic inspection, staining methods and by evaluating the expression level of some critically relevant genes. The growth inhibition was correlated with down-regulation of the catalytic subunit of telomerase (hTERT) gene (p < 0.01) and the corresponding reduction of telomerase activity in sub-cytotoxic concentrations of boldine (p < 0.002). However, various modes of cell death were stimulated, depending on the concentration of boldine. Very low concentrations of boldine over a few passages resulted in an accumulation of senescent cells so that HepG-2 cells lost their immortality. Moreover, boldine induced apoptosis concomitantly with increasing the expression of bax/bcl2 (p < 0.02) and p21 (p < 0.01) genes. Boldine might thus be an interesting candidate as a potential natural compound that suppresses telomerase activity in non-toxic concentrations.
Highlights
The terminal DNA at chromosome ends, known as telomeres, progressively shorten during each cell division and limit the replicative lifespan of dividing cells [1]
We believe that potential telomerase inhibitors and telomere-interfering compounds can be found among plant secondary metabolites, which mainly serve as defensive compounds that protect plant cells against various stresses
In MCF-7 cells, the down-regulation of telomerase by the alkaloid harmine induced an overexpression of p53/p21 pathway resulting in an accelerated senescence phenotype of the cancer cells [40], similar to the results seen in our boldine experiments
Summary
The terminal DNA at chromosome ends, known as telomeres, progressively shorten during each cell division and limit the replicative lifespan of dividing cells [1]. It is believed that the continuous proliferation and avoidance of replicative senescence in many cancer cells correlates with their ability to maintain their telomeres by activation of telomerase. This ribonucleoprotein is a special reverse transcriptase that carries out the elongation of telomeres in most immortal cells [2]. In our preliminary screening of anti-telomerase compounds among plant secondary metabolites [7,8,9], boldine (1,10-dimethoxy-2,9-dihydroxyaporphine, Figure 1), a natural aporphine alkaloid found mainly in the Chilean medicinal plant Peumus boldo showed a dose- and time-dependent antiproliferative effect in several cells. This study was focused on an evaluation of the cytotoxicity and antiproliferative effect of this compound with special reference to telomerase inhibition and induction of apoptosis
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