Steroidal glycoalkaloids present in Solanaceae are toxic compounds biosynthesised for the protection of the plants. However, many health benefits of these compounds have been reported so far. One of their promising targets might be cancer, as demonstrated in a large number of studies. However, the main mechanism of action seems to be unclear. It could include the induction of apoptosis or trigger a necrosis with a subsequent inflammatory response. The relatively high systemic toxicity of steroidal compounds is another effect that must be taken into account in anticancer research. The main aim of this work was to summarise the recent progress in the investigation of the mechanisms of their antitumour action and to discuss their potential.
- MeSH
- alkaloidy Solanaceí izolace a purifikace farmakologie toxicita MeSH
- fytogenní protinádorové látky izolace a purifikace farmakologie toxicita MeSH
- lidé MeSH
- rostlinné extrakty izolace a purifikace farmakologie toxicita MeSH
- Solanaceae chemie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Alpha-tomatine is a major glycoalkaloid found in the roots, leaves, stems and fruit of tomatoes Lycopersicon esculentum . Recently, alpha-tomatine has been recognized as a potential anticancer drug. In the present study, we identified the signaling cascades involved in the antitumor effect of alpha-tomatine on MOLT-4 leukemic cells. Alpha-tomatine inhibited the proliferation and decreased the viability of MOLT-4 cells in a dose-dependent manner. An increase in the activity of caspases 9 and 3/7 was not observed. However, an increase in the amount of p53 and its phosphorylation on serine 15, as well as an increased amount of mitochondrial protein PUMA was detected 4 and 24 h after exposure to alpha-tomatine at a concentration of 1–3 μmol/l. Inhibition of the proliferation of MOLT-4 cells by alpha-tomatine is also associated with an increase in p21 WAF1/CIP1 and the activation of Chk2. The comet assay did not detect significant amounts of single or double DNA strand breaks in cells treated with alpha-tomatine at concentrations of 0.1–9 μmol/l. Our results thus contribute to the understanding of the anticancer action of alpha-tomatine.
- Klíčová slova
- chk2, checkpoint kinase 2,
- MeSH
- apoptóza účinky léků MeSH
- buněčná smrt účinky léků MeSH
- kometový test MeSH
- leukemie T-buněčná * farmakoterapie MeSH
- nádorové buněčné linie MeSH
- nádorový supresorový protein p53 * analýza metabolismus účinky léků MeSH
- onkogenní protein p21(ras) MeSH
- poškození DNA MeSH
- proliferace buněk účinky léků MeSH
- protein-serin-threoninkinasy metabolismus MeSH
- protinádorové látky MeSH
- průtoková cytometrie MeSH
- Puma MeSH
- replikace DNA MeSH
- statistika jako téma MeSH
- techniky in vitro MeSH
- tomatin * analogy a deriváty terapeutické užití MeSH
- western blotting MeSH
In recent years, α-tomatine has been studied for its anticancer activity. In the present study, we focused on the cytotoxic effect of α-tomatine in the MCF-7 human breast adenocarcinoma cell line, its mechanism of action, biotransformation and stability in the culture medium. We observed an inhibition of cell proliferation and viability at concentrations of 6 and 9 µM but then a recovery of cells occurred. The recovery was not caused by the biotransformation of α-tomatine in MCF-7 cells, but by a substantial decrease in the concentration of α-tomatine in the culture medium due to its binding with cholesterol. Regarding the mechanism of action of α-tomatine, we observed no DNA damage, no changes in the levels of the proteins p53 and p21(WAF1/Cip1), and no apoptosis (neither activated caspase-8 and -9, nor sub-G1 peak, or morphological signs). We found a loss of ATP in α-tomatine-treated cells. These results support the conclusion that α-tomatine does not induce apoptosis in the MCF-7 cell line.
- MeSH
- apoptóza účinky léků MeSH
- buněčný cyklus účinky léků MeSH
- cholesterol metabolismus MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- nádorový supresorový protein p53 metabolismus MeSH
- nádory prsu farmakoterapie metabolismus patologie MeSH
- proliferace buněk účinky léků MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- tomatin aplikace a dávkování analogy a deriváty MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
AIM: To evaluate the anticancer effect of alpha-tomatine (i.p.) either alone or in combination with doxorubicin (i.v.) in a mouse tumour model. METHODS: We studied the effect of repeated alpha-tomatine (0.1 - 9 mg/kg) and/or doxorubicin (2 mg/kg) on the growth and mitotic activity of the solid Ehrlich tumour in vivo, as well as on the survival of the tumour-bearing mice. RESULTS: Monotherapy with alpha-tomatine had a significant dose-dependent anticancer effect which peaked at 1 mg/kg. This was shown by both slowed tumour growth and reduced tumour cell proliferation. We also provide the first evidence that the combination alpha-tomatine (1 mg/kg) and doxorubicin (2 mg/kg) had a synergistic effect and significantly prolonged the survival of the mice. Neither alpha-tomatine nor doxorubicin influenced the infiltration of tumours with CD3+ lymphocytes; nor were we able to find an in vivo modulation of the key molecules of two regulatory pathways reported in vitro as the principal anti-cancer mechanisms of alpha-tomatine, i.e. iNOS and phosphorylated ERK2. However, alpha-tomatine still led to intracellular DNA inhibition and protein synthesis in Ehrlich tumour cells in a short-term culture ex vivo with IC50 values of 8.7 and 6.6 µM. CONCLUSIONS: The results suggest that ΤΟΜ, especially in combination with doxorubicin, may be a promising agent for the treatment of malignant solid tumours. Despite growing knowledge of the mechanisms of ΤΟΜ action in cancer cells, most aspects remain unclear. Parallel organ toxicity, especially potential liver effects, requires careful attention when performing in vivo studies in the future.
- MeSH
- bilirubin krev MeSH
- biologické markery metabolismus MeSH
- doxorubicin aplikace a dávkování MeSH
- Ehrlichův tumor farmakoterapie metabolismus MeSH
- experimentální nádory mléčných žláz farmakoterapie metabolismus MeSH
- játra účinky léků MeSH
- myši MeSH
- proliferace buněk účinky léků MeSH
- protinádorová antibiotika aplikace a dávkování MeSH
- tomatin aplikace a dávkování analogy a deriváty farmakologie MeSH
- western blotting MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
45 s. : tab. + 5 s. příl.
