Abstract
The search for effective plant-derived anti-cancer agents or their synthetic analogs has continued to gain interest in drug development. The anti-cancer activity of parthenolide (PTL) isolated from Tanacetum parthenium, has been attributed to the presence of α-methylene-γ-lactone skeleton. In the present study we aimed to investigate the anti-cancer potential of a new synthetic compound, 3-isopropyl-2-methyl-4-methyleneisoxazolidin-5-one (MZ-6), with the same as in PTL α-methylene-γ-lactone motif, on two breast cancer cell lines, MCF-7 and MDA-MB-231. For comparison, PTL was included in the study. PTL and MZ-6 reduced the number of viable MCF-7 and MDA-MB-231 cells, with half maximal inhibitory concentration values between 6 and 9 μM. Both compounds dose-dependently inhibited incorporation of [3H]thymidine, up-regulated Bax and down regulated Bcl-2 mRNA. The levels of the end product of lipid peroxidation, malondialdehyde, were significantly higher. In MCF-7 cells, MZ-6 induced early apoptosis and cell cycle arrest in G0/G1 phase. The effect produced by MZ-6 was much stronger compared with PTL. In MDA-MB-231 cells, both tested compounds had similar effect and induced mostly late apoptosis. In conclusion, the observed anticancer activity makes MZ-6 an attractive drug candidate and shows that simple analogs of α-methylene-γ-lactones can be good substitutes for more complex structures isolated from plants.
Highlights
Breast cancer is one of the leading causes of mortality among women in developed countries
Janecki Institute of Organic Chemistry, Technical University of Lodz, Lodz, Poland simple analogs of a-methylene-c-lactones can be good substitutes for more complex structures isolated from plants
Since the induction of apoptosis might be mediated through the cell cycle arrest, we examined the effect of PTL and MZ-6 on cell cycle perturbations
Summary
Breast cancer is one of the leading causes of mortality among women in developed countries. 60 % of breast cancers are hormone-dependent and require estrogen for tumor growth [1]. Recent progress in diagnosis and therapy has increased the survival of women with estrogen-dependent breast cancer. In recent years the search for new anti-tumor substances obtained from plants has been a hot research activity. The sesquiterpene lactone, parthenolide (PTL), isolated from feverfew (Tanacetum parthenium) has been extensively studied in relation to its anti-cancer properties. PTL was shown in vitro to inhibit proliferation and induce apoptosis in various human cancers, such as colorectal cancer, hepatoma, cholangiocarcinoma and pancreatic cancer [2,3,4,5], but there have been no reports on its ability to induce apoptosis in breast cancer cells. The active fragment in the structure of PTL is an a-methylene-c-lactone skeleton which can react via the Michael type addition with mercapto groups of enzymes
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