Preposterous: Platinum Edition

I am like a kid with too many toys to play with. Except the toys are areas of interest. Oooo cancer genes! Oooo new Porsche edition! Oooo syphilis! Oooo Russian political infighting! Ooooo chemotherapy drugs! Yeah, this is my brain but not as bad as in real life. So what am I on about today you ask? Just kidding, no one asked. But its cisplatin thanks. It's like the meme of "literally no one:........." "Me: ever been abducted by aliens and do you think that has anything to do with the fact you can't even keep the weed in your yard alive?" Me in a nutshell. Peanut shell please. I love peanut butter.

Ah yes, cisplatin. I decided on this rabbit hole after reading and listening to a few articles and podcasts about cancer. Cisplatin came up a lot in those studies as one of the more popular chemotherapeutic agents. Popular might be an understatement, uses include (on and off label): advanced ovarian, testicular, bladder breast, cervical, endometrial, esophageal, gastric, lung, penile, bone, and lymphoma cancers to name a few. That is an impressive resume to be sure. It can be used as neoadjuvant therapy, in combination with other chemo drugs, targeted therapy, and immunotherapy, and with surgery, radiation, and/or alone. How does it do this? It sounds like the Toyota Tacoma/Hilux of cancer drugs. 

Cisplatin is cytotoxic, that is it kills cells, via the platinum binding to DNA bases and causing damage. One the DNA repair mechanisms fails to repair the platinum infiltrated DNA, the cell gets apoptosed. Yes I made that word up. This favors death to rapidly dividing cells, usually cancer. It can be given IV and as an intraperitoneal agent. Cisplatin really is a jack of all trades. 

Cancer cells may get hip to the machinations of cisplatin and come up with ways of resistance. Some articles I read cited 50% of cancers treated with cisplatin will develop resistance. With recurring cancers after treatment, resistance is even higher. There are four main classifications of resistance that include pre target, on target, post target, and off target. 

Pre target, that is before incorporating into the DNA of a cell to cause death, cells can reduce the influx of cisplatin, or increase the explosion. Cisplatin reduces the expression of some proteins that allow for the transportation into the cell, locking its own door without a key. This can be for specific transporters that also reduce intake of glucose or other compounds. Other times the cell will produce compounds that bind with the cisplatin before it reaches the DNA using some magic chemistry stuff. 

On target resistance involves "putting out the fire" once cisplatin has made it to the DNA. The cell can mutate to repair the damage, tolerate the damage, to remove the platinum from the DNA. Post target resistance affects the pathways that lead to apoptosis after the platinum has made it into the DNA. Basically not killing the cell even though a mistake has been made. Off target resistance has to do with parts of the cell not related to the effects of cisplatin but end up effecting the drug by chance. This can include the production of antioxidants in the cell or regulations on how the cell responds to stress. 

There are some words I do not understand on epigenetic and how different genes play a role even aside from those discussed above. These and other mechanisms of resistance can be specific to certain types of cancer. What I find really interesting is the effect of turning certain genes "on or off" and the effects that has on not only cisplatin resistance, but resistance to other drugs too. In the small in vitro studies I read, the authors could de or reactivate genes to shift from resistance to sensitive and back again. 

It looks like immune therapy and targeted therapies are the next steps in cancer treatment, but I think there will always be a place for "regular" cancer treatments. Perhaps there will be drugs or vaccines or other compounds that will target the genes that promote cisplatin resistance? Could this be used for antibiotic resistance as well? Whatever solution we come up with, it is evolution that drives resistance and I would hypothesize that even if we can turn these genes on and off, resistance will for despite our advances. I don't want to sound fatalistic, and perhaps one day all cancers will be curable. Until that time, research is moving the frontline forward inch by inch. 

I hope you thought that was somewhat interesting! I did, which is why I wrote this of course. Please share this and the podcast if you like either of them. Love y'all.. 

References 

Cisplatin-Based Chemotherapy of Human Cancers from Journal of Cancer Science & Therapy by Brown et al., in 2019.

Cisplatin Resistance: A Cellular Self-Defense Mechanism Resulting from Multiple Epigenetic and Genetic Changes from Pharmacological Reviews by Shen et al., in 2012.

Cisplatin Resistance: Genetic and Epigenetic Factors Involved by Lugones et al., in Biomolecules 2022. 

Image of a skeletal model of cisplatin from Wikipedia.

The Role of Tumor Metabolism in Cisplatin Resistance by Wang et al., in Frontiers in Molecular Biosciences 2021.