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Selective inhibition of parallel DNA damage response pathways optimizes radiosensitization of glioblastoma stem-like cells

Glioblastoma (GBM) is the most common form of primary brain tumor in adults that is essentially incurable. Despite aggressive treatment regimens centered on radiotherapy, tumor recurrence is inevitable and thought to be driven by GBM stem-like cells (GSCs) that are highly radioresistant. DNA damage response pathways are key determinants of radiosensitivity, but the extent to which these overlapping and parallel signaling components contribute to GSC radioresistance is unclear. Using a panel of primary patient-derived GBM cell lines and clonogenic survival assays, we confirmed that GSCs were significantly more radioresistant than paired tumor bulk populations. DNA damage response targets ATM, ATR, CHK1, and PARP-1 were upregulated in GSCs, and CHK1 was preferentially activated following ionizing radiation. Consequently, GSCs exhibited rapid G2/M cell cycle checkpoint activation and enhanced DNA repair. Inhibition of CHK1 or ATR successfully abrogated G2/M checkpoint function,
leading to increased mitotic catastrophe, but modestly increased radiation sensitivity. Conversely, ATM inhibition exerted dual effects on cell cycle checkpoint regulation and DNA repair that were associated with greater radiosensitizing effects than inhibition of CHK1, ATR or PARP alone. Combined PARP and ATR inhibition resulted in profound radiosensitization of GSCs that was greater than in bulk populations and also exceeded the effect of ATM inhibition. These data demonstrate that multiple, parallel DNA damage signaling pathways contribute to GSC radioresistance and that combined inhibition of cell cycle checkpoint and DNA repair targets provides the most effective means to overcoming therapy resistance.

Does caffeine fight cancer?

Epidemiological studies have shown that caffeinated drinks may help prevent skin cancer by inhibiting a DNA repair pathway, thus killing potentially precancerous cells. In English, it means that drinking drinks containing caffeine will reduce one’s chances of developing some types of cancer, including UV-associated skin cancer. That just proves that caffeine fight cancer. The results, published in the Proceedings of the National Academy of Sciences, lend support to the idea that caffeine could be added to sunblock to increase its protective effects. At the cellular level, they’re showing that caffeine is working in this way of inducing an apoptotic mechanism. This statement was then made by cancer epidemiologist Joanne Kotsopoulos of the University of Toronto.

In the 2007, a study stated that woman who drank caffeinated coffee on a daily basis had a 10 percent lower risk of nonmelanoma skin cancer. Six or more cups of coffee a day translated to a 30 percent reduction in risk. Mouse studies have also confirmed the link, with both ingested and topically-applied caffeine lowering skin cancer rates in the animals. But exactly how the stimulant protected against cancer remained mysterious. One possibility is the drug’s inhibition of ataxia telangiectasia and Rad3-related (ATR), a large protein kinase that senses incomplete DNA replication often a result of DNA damage and signals the cell to not divide. By inhibiting ATR activity, caffeine could make cells more likely to die in response to UV damage, preventing damaged cells from ever becoming cancerous.

Studies have shown that the caffeine molecule acts as a sunscreen. It therefore blocks the penetration of UV rays. And that is why today we see many sunblocks with a good amount of caffeine in them.

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Can sugar consumption cause breast cancer?

A recent study stated that drinking three sugar sweetened drinks a week would increase the risk of having breast cancer. The study had 776 pre-menopausal women and 779 post-menopausal women. Each women’s breast density was assessed by examining their mammograms. The women were told to make a note of sweet they consumed such as chocolates, cakes, ice cream or any sweet drinks. Also they were asked to make a note of how much of spoonful of sugar they add to the drinks.

It was then found out that post-menopausal women who consumed more of sugar, an increase in the density of breast. While the pre-menopausal women observed an increase in breast density when they consumed sugar food. These women, in a week were just consuming three sugar sweetened drinks. The study then further stated that sugar tends to increase the migration of breast cells together. This explains the fact that the premenopausal women who consumed sugar-sweetened drinks were 3 percent more likely to have dense breasts than those who didn’t consume the drinks. And having dense breasts increases your risk of breast cancer by making it difficult to see tumors on mammograms.

However, there is more to be studied on this matter. But until then there is still a link between the sugar consumption and breast density. About 40% of women in the US have dense breast and they are totally unaware of it. Doctors say that women with a dense breast are five time more likely to have a breast cancer and 10 times more likely to miss the tumor in the mammogram test.

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