RESISTANCE AND SENSITIVITY; COMPETITIVE MECHANISMS OF CISPLATINAbstract
In the battle against cancer, platinum drugs have contributed a lot so far but still the prerequisite is to mend their flaws e.g., resistance and reduced sensitivity. In addition to side effects, intrinsic and acquired resistance decreases the effects of cisplatin on cancer cells by lowering the formation of DNA adducts and subsequent DNA damage. Resistance against cisplatin includes; the increased DNA repair of cisplatin induced DNA adducts by MMR, NER pathways, increased tolerance, and interaction with cellular proteins instead of DNA resulting in cellular detoxification of cisplatin, and, decreased accumulation of drug due to abnormal role of efflux and influx pumps. With therapy of cisplatin survival pathways (Akt, MKPI) are also triggered, occasioning in the activation of NF-kb, XIAP that subsidizes to cisplatin resistance. Development of new platinum compounds that can combat with the intrinsic and acquired drug resistance would be the promising strategy in the cancer therapeutic field. Combination or adjuvant therapies of cisplatin with gemcitabine, etoposide, topotecan etc. have been shown to reduce the cellular resistance by upsetting the DNA repair pathways. Furthermore, use of kinase inhibitors along with cisplatin would hinders MAPK and other pathways that are usually actuated by oxidative stress prompted by cisplatin.
Maria Fareed Siddiqui* and Esha Sadiq
Centre for Research in Molecular Medicine (CRiMM), The University of Lahore, 1 km Defense Road Lahore, Pakistan
22 January, 2015
16 March, 2015
18 April, 2015
01 August, 2015