- Prof. Pradip K. Mascharak
- Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, USA.
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Special Issue Introduction
The serendipitous discovery of Cisplatin [cis-diamminedichloroplatinum (II)] as an anticancer drug brought a paradigm shift in cancer chemotherapy. Since its approval by FDA in 1978, this small inorganic platinum complex has been successfully employed in the treatment of numerous human cancers including bladder, head and neck, lung, mesothelioma, ovarian, esophageal and testicular cancer. Since its introduction many platinum analogs have been synthesized, either to bypass resistance or reduce toxicity. However, only carboplatin has replaced cisplatin for treatment of several cancers, while oxaliplatin is one of the standard drugs for treatment of colorectal cancer and pancreatic cancer. The drug action has been linked to its binding to the N7 reactive center on adenine and guanine residues, forming intra- and interstrand cross-links (GpG and ApG adducts), leading to deoxyribonucleic acid (DNA) damage in cancer cells, blocking cell division and resulting in apoptotic cell death. Cisplatin, carboplatin and oxaliplatin are usually combined with other chemotherapeutics, such as gemcitabine, paclitaxel, docetaxel, 5-fluorouracil, irinotecan, doxorubicin, bleomycin, pemetrexed and methotrexate, for better treatment outcomes. Unfortunately, despite cisplatin’s (and its registered analogs) superiority among other tolerable chemotherapies, the most common impediment of platinum-based chemotherapy is chemoresistance which often is present at the beginning of treatment in a large number of patients.
The mechanisms of platinum resistance have been explored by many research groups around the world. Some of the pathways by which chemoresistance arises in tumor cells have been identified. These include (a) increased repair of platinum-DNA; adducts, e.g. by excision-repair enzymes (ERCC1) and mismatch repair; (b)reduced expression of the tumor protein 53 binding protein 1 (53BP1); (c)inhibition of DNA-dependent protein kinase protein (DNA-PKcs); (d) glutathione-dependent antioxidative dysfunction through inhibition of enzymes such as cystathionine beta-synthase; (e) downregulation of cellular apoptosis-associated proteins, Bax/Bcl-2 and caspase 3; and (f) inhibition of ferroptosis that augments the efficacy of cisplatin.
As expected, treatment strategies to overcome chemoresistance in tumor cells to cisplatin have also been formulated, since many mechanisms of chemoresistance have been identified. For example, resistance to cisplatin has been mitigated by combination therapy (such as with gemcitabine, paclitaxel or doxorubicin). Replacement of cisplatin with second generation of platinum-based drugs such as carboplatin or oxaliplatin were usually administered to lower or change side effects, while oxaliplatin is not inactivated by mismatch repair and is therefore used for treatment of colorectal cancer.Lobaplatin is only registered in China. Glutathione-responsive prodrugs such as glutathione tripeptide have been used to enhance cisplatin drug release in tumors. Naturally derived bioactive products such as phytochemicals and flavonoids have also been investigated in the combination. Some of these compounds have been shown to improve active transport of the drug into the cell and/or inhibit its export out of the cell. Compounds such as curcumin induce apoptosis by downregulating anti-apoptotic proteins such as Bcl2 and survivin. A number of compounds that act on the Warburg Effect through inhibition of critical Warburg enzymes such as glucose transporter 1 (GLUT1), pyruvate dehydrogenase kinases (PDKs) or pyruvate kinase M2 (PKM2) also enhance cisplatin-based therapy. Finally, liposome-trapped platinum drugs have recently been tested to restore cisplatin sensitivity. This special Issue on “Mechanism of platinum Resistance and Reversal Strategies” will not only report on recent novel strategies used to mitigate chemoresistance to platinum analogs but also will present provocative hypothesis-derived combination formulation(s) for better outcomes of platinum therapy in various cancer treatments.
Submission Deadline31 May 2023