It has been shown by Fulda et al. that the naturally occurring compound resveratrol (a polyphenol found in grapes and red wine) can be used as a sensitizer for anticancer drug-induced apoptosis by the action of causing cell cycle arrest. This cell cycle arrest causes a dramatic decline in survivin levels in the cells, as it is known from the literature that survivin expression is highly linked with the cell cycle phase state. Thus, the decrease in survivin, which is a contributing factor to chemotherapy resistance and apoptosis induction therapies, would render the cancer cells more prone to such cancer treatments. Fulda et al. have demonstrated the benefits of resveratrol through a series of experiments. First, the authors of the paper tested the intrinsic cytotoxic effects of resveratrol. They found that it induced moderate apoptosis levels only in SHEP neuroblastoma cells. After, they tested resveratrol in combination with several different known anticancer agents. They found a consistent increase in the level of apoptosis induced by the drugs when resveratrol was also present. Moreover, they varied the order with which either the drugs or resveratrol was introduced to the cancer cells to determine whether the sequence of treatment had any important effect. It was found that the highest levels of apoptosis induction were observed when resveratrol was added prior to anticancer drug treatment. Next, the authors tested for any differential sensitivity to apoptosis linked to the phase of the cell cycle the cells were in. Analysis by flow cytometry revealed an accumulation of cells in S phase upon treatment with resveratrol. The cells were also halted in different phases of the cell cycle using special compounds and then treated with the anticancer drugs. They found that cells halted in S phase were significantly more sensitive to the cytotoxic effects of the drugs.
To determine the involvement of survivin in resveratrol-mediated sensitization, the authors decided to test whether downregulation of the specific survivin protein expression would confer a similar effect on the phenotype of resveratrol-treated cells. In terms of seeing at which level resveratrol worked, they did a northern blot and found that resveratrol treatment resulted in a decrease in survivin mRNA levels, thus implying resveratrol's inhibitory action at the transcriptional level. To further see whether survivin played a key role in sensitization of the cancer cells to cytotoxic drugs, survivin antisense oligonucleotides were used to knock down any survivin mRNA, and, thus, its possibility to be translated is also eliminated. siRNAs for survivin are complements in sequence to the mRNA sequence encoding survivin. When these siRNAs for survivin are introduced into cells, they will bind to the respective complementary mRNA and, thus, prevent its translation since the mRNA is now impeded from proper physical interaction with the translational machinery. In this way, the siRNAs for survivin effectively downregulates survivin expression level in the cell. Cells treated with antisense oligonucleotides for survivin showed similar sensitization to cytotoxic drugs as cells treated with resveratrol, which offers support for the mechanism of action of resveratrol.