Repozytorium publikacji - Politechnika Gdańska

It is ell established that many tumor types contain a fraction of cells, with stem cell-like properties, called cancer stem cells (CSCs), that are resistant to apoptosis induced by therapeutic agents. The presence of CSCs may explain why a standard anticancer treatment, that eliminates only differentiated cancer cells, does not lead to cancer cure.We previously showed the existence of caffeine-sensitive mechanism that controls the number of cancer stem cells (CSCs) in lung tumor cell population. To characterize these molecular mechanism, we have developed tumor A549-Caff cells which are able to grow in the continuous presence of 1mM caffeine and become about 3-fold resistant to the drug. Caffeine-resistant cells have decreased cell doubling time and changed sensitivity to standard antitumor drugs. For some drugs (SN-38, cisplatin, etoposide) caffeine resistant A549 cells showed increased sensitivity, for other (ICRF-187) these cells were about 3-fold crossresistant.We observed that caffeine transiently induces DNA damage pathway and production of reactive oxygen species (ROS) as revealed by the oxidation-sensitive fluorescent probe H2DCFDA. Production of ROS by caffeine was not ibserved in A549-Caff cells. We also noticed that the morphology and number of mitochondria were changed in caffeine-resistant cells. In addition, transmembrane mitochondrial potential was greatly increased in A549-Caff cells, however, total ATP production was similar for both cell types. Measurements of surface oxygen consumption showed increased activity of the glycolytic pathway in A549-Caff cells. Interestingly, the SP population in A549-Caff cells decreased to 2% of total cells compared to about 10% observed in A549 cells. This was accompanied by lower fraction of stem cells in caffeine-resistant cell population.In conclusion, we show here that exposure of A549 cells to caffeine leads to changes in the respiratory metabolism and decreased fraction of both SP-cells and CSCs. This can be related to the inhibition of CSC differentation and possibly their self-renewal. We propose that caffeine or other compounds that mimic caffeine action may by used in innovative cancer therapies which are based on small molecular weight inhibitors of CSC differentiation and self-renewal.

Autorzy

• dr inż. Marcin Serocki link otwiera się w nowej karcie ,
• Michał Sabisz link otwiera się w nowej karcie ,
• prof. dr hab. inż. Andrzej Składanowski link otwiera się w nowej karcie