Shrestha Sherry Chakraborty, Amity University Kolkata
Cancer is marked by the uncontrollable growth of malignant cells which then spread by metastasizing to different regions of the body. To battle against this deadly disease, a variety of treatments have evolved with years of research and development overcoming complex challenges and hurdles. The most well known of which is Chemotherapy. However, drug resistivity is a troublesome phenomenon in which diseases become resistant to the very treatment that is supposed to cure or exterminate it. The first instance of drug resistance was found when bacteria were found to resist treatment to certain antibiotics. Drug resistance can occur in a huge number of ways and they are:
Drug Inactivation–
After a drug is incorporated it must be activated to reach its efficiency. However, some cancer drugs, are very feebly activated. Thus often leading to a potential inactivation. One such example was observed during the treatment of acute myelogenous leukaemia, with cytarabine which after many metabolic reactions is converted to AraC-triphosphate. A mutation in the pathway often resulted in the decreased activation and thus this gradually resulted in the development of resistivity.
Alteration of Targets-
Drugs often target specific molecular components for their functionality and activity. Any change in the drugs’ target causes drug resistance in case of malignant cells. One such example is the target topoisomerase II, that is targeted by drugs. The drugs cause the stability of DNA and the topoisomerase complex where it leads to further DNA damage and halts in the cell cycle. In this case, if a mutation is present in the topoisomerase II gene, drug resistance will occur.
Efflux-
Drug efflux is a process by which excess accumulation of drugs is prevented in the cells through an efflux mechanism. The efflux is made possible by the transporter proteins of the ABC family in the plasma membrane of cells. They are transmembrane proteins that transport various substances across the membrane. Due to the presence of these proteins excess toxins do not accumulate inside cells. However, they also play an important role in drug resistance. There are generally three transporters, namely multidrug resistance protein 1, multidrug resistance-associated protein 1, and a breast cancer resistance protein, which plays an important role in resistance. These can efflux a wide variety of drugs including those that are incorporated into the body to treat cancer thus protecting malignant cells from Chemotherapy.
Repair of DNA Damage-
Chemotherapeutic drugs work by damaging DNA directly or indirectly. However, sometimes these damages are reversed by DNA repair. For example, Cisplatin is a platinum-containing chemotherapy drug which causes harmful DNA crosslinking. However, this is often repaired by the help of basic DNA repair mechanisms like homologous recombination, leading to the development of resistance in these cells for these types of drugs.
How can we combat drug resistance in case of Cancer?
Although combating drug resistance is a challenging approach, with the use of cancer proteomics and cancer genomics, it is possible to identify relevant genes, that cause drug resistance. Personalized therapy is often recommended because there are a large number of genes with different mutations. The immediate and most effective solution would be to constantly monitor the patient and treat them with chemotherapeutic drugs when required. When drug resistance is being treated using only one drug, this may lead to treatment failure as the more sensitive cells could die and the fit cells would proliferate. We can also block energy to cancer cells for their proliferation. Although many theoretical ways are available to combat drug resistance, the practicality of it working in real-life remains an endless game to prevent drug resistance in malignant cells still to this day.
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Source:
1. Mansoori, B., Mohammadi, A., Davudian, S., Shirjang, S., & Baradaran, B. (2017). The different mechanisms of cancer drug resistance: A brief review. Advanced Pharmaceutical Bulletin, 7(3), 339–348. https://doi.org/10.15171/apb.2017.041
2. Lantermann, A. B., & Sharma, K. J. M. and S. V. (2015, July 31). The role of epigenetics in drug resistance in cancer. Epigenetic Diagnosis & Therapy (Discontinued). https://www.eurekaselect.com/140432/article.
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