Week 5 – Just some theory

So this week, I didn’t spend much time at the lab, mainly so I could compile all my results and begin the analysis part. But what good is analysis without understanding the theory behind this drug combination therapy?

Let’s start with p53, the most important tumor suppressor ever. In normal cells, p53 protein expression is “normal” or relatively low, because you don’t have any need to halt the cell cycle. In cancer cells, p53 proteins are heavily expressed because of their effort to regulate the cell cycle. At the same time, the p53 gene is also mutated, so while the mutated p53 protein is expressed, it has no function, which is why cell proliferation continues. Now p53 makes cells perform 3 major functions – growth/development arrest, DNA repair, and apoptosis. In my project, I’m focusing on apoptosis, because that’s how the body exterminates cancer cells. Now the actual process in how p53 expression leads to those 3 functions is a bit too detailed and will be discussed in my final presentation. Nevertheless, keep the above information in mind.

Now, let’s move on to information about the two drugs I’m testing. Doxorubicin is a very commonly used chemotherapeutic drug, and it’s not selective to any type of cancer. It’s also known to cause cardiac toxicity when used at high dosages, because of that non-selectiveness. Now you may be wondering why I’m testing this especially toxic, particular one if it’s already being used. Just keep in mind that it’s the combination therapy that matters. What Dox does is stabilize p53 release, that way we don’t have an up-regulation of mutated p53 or a down-regulation of wild-type p53. It targets dividing cells by activating p53, which in turn triggers the apoptotic cycle. Unfortunately, in order to clear the body of cancer cells, Dox has to be administered at high dosages, which is too toxic. Paclitaxel is normally used to treat breast cancer and small lung cancers. It has been shown to block liver cancer cells at the G2/M phaseof the cell cycle, but it’s not strong enough to actively promote apoptosis. This is why we are combining both Dox and Pac. Pac stops the evading cancer cells at the G2/M phase, and then it induces apoptosis in those cells. Now all the cancerous, proliferating cells that are actively dividing, are targeted by Dox. This way, we lower the Dox dose, and lower cardiac toxicity.

Thanks for attending my Ted Talk.