Abstract
Betulin (BT) is a natural pentacyclic lupane-type triterpene exhibiting anticancer activity. Betulin derivatives bearing propynoyloxy and phosphate groups were prepared in an effort to improve the availability and efficacy of the drug. In this study, a comparative assessment of the in vitro anticancer activity of betulin and its four derivatives was carried out using two human breast cancer cell lines: SK-BR-3 and MCF-7. In both studied cell lines, 30-diethoxyphosphoryl-28-propynoylbetulin (compound 4) turned out to be the most powerful inhibitor of growth and inducer of cellular death. Detailed examination of that derivative pertained to the mechanisms underlying its anticancer action. Treatment with compound 4 decreased DNA synthesis and up-regulated p21WAF1/Cip1 mRNA and protein levels in both cell lines. On the other hand, that derivative caused a significant increase in cell death, as evidenced by increased lactate dehydrogenase (LDH) release and ethidium homodimer uptake. Shortly after the compound addition, an increased generation of reactive oxygen species and loss of mitochondrial membrane potential were detected. The activation of caspase-3 and fragmentation of genomic DNA suggested an apoptotic type of cell death. However, analysis of cellular morphology did not reveal any nuclear features typical of apoptosis. Despite necrosis-like morphology, dead cells exhibited activation of the cascade of caspases. These observations have led to the conclusion that compound 4 pushed cells to undergo a form of necrotic-like regulated cell demise.
Highlights
Pentacyclic lupane-type triterpenes are an interesting class of naturally occurring substances with a wide range of biological properties
BT has been shown to exert cytotoxicity against some human neoplastic cell lines derived from cervical (HeLa), liver (HepG2, SK-HEP-1), lung (A549), and breast (MCF-7) cancers, as well as melanoma
We found that 28-propynoylbetulin quite efficiently induced growth arrest and cell death in the SK-BR-3 cell line, but MCF-7 cells were substantially insensitive to that substance
Summary
Pentacyclic lupane-type triterpenes are an interesting class of naturally occurring substances with a wide range of biological properties. Betulin (lup-20(29)-ene-3β,28-diol) is a triterpenoid widely distributed in plants that is abundant in the outer bark of birch trees (up to 30% of dry weight) [2]. This raw material is readily available as a waste by-product in the wood industry, whereby BT can be extracted on a large scale. Rzeski et al [1] reported that primary cultures of various neoplastic cells were more sensitive to BT treatment than established tumor cell lines. The anticancer activity of BA, a product of BT oxidation, has been proven in several studies, using both in vitro and animal models [7,8]. There is a growing body of evidence that the anticancer action of both substances is mediated mainly via apoptosis induction [9,10]
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