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Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment

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Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment International Journal of Molecular Sciences Review Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment Robert Csaba Kiss, Fen Xia and Scarlett Acklin * Department of Radiation Oncology, Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; [email protected] (R.C.K.); [email protected] (F.X.) * Correspondence: [email protected]; Tel.: +1-(919)-613-4382 Abstract: Platinum-based chemotherapies, such as cisplatin, play a large role in cancer treatment. The development of resistance and treatment toxicity creates substantial barriers to disease control, yet. To enhance the therapeutic index of cisplatin-based chemotherapy, it is imperative to circumvent resistance and toxicity while optimizing tumor sensitization. One of the primary mechanisms by which cancer cells develop resistance to cisplatin is through upregulation of DNA repair pathways. In this review, we discuss the DNA damage response in the context of cisplatin-induced DNA damage. We describe the proteins involved in the pathways and their roles in resistance development. Common biomarkers for cisplatin resistance and their utilization to improve patient risk stratification and treatment personalization are addressed. Finally, we discuss some of the current treatments and future strategies to circumvent the development of cisplatin resistance. Keywords: anticancer drugs; cisplatin; DNA damage response; cisplatin resistance Citation: Kiss, R.C.; Xia, F.; Acklin, S. Targeting DNA Damage Response 1. Introduction and Repair to Enhance Therapeutic Since receiving Food and Drug Administration (FDA) approval in 1978 [1], the widely Index in Cisplatin-Based Cancer known platinum-based chemotherapy, cisplatin, has gained clinical indications for the Treatment. Int. J. Mol. Sci. 2021, 22, treatment of a broad spectrum of cancers including multiple myeloma, lung, breast, colorec- 8199. https://doi.org/10.3390/ tal, gynecologic, and head and neck cancers [1,2]. While cisplatin confers strong cytotoxic ijms22158199 activity, especially in combination with other treatment modalities, such as radiotherapy or surgery [3], the development of drug resistance represents one of the major obstacles Academic Editor: Erica Gentilin to the cure of cancer. Even tumors that are initially sensitive to cisplatin may later re- lapse and develop mechanisms to evade growth restriction and cell death [2]. Cancer Received: 6 July 2021 control can be further hindered when cisplatin-induced toxicities lead to dose reduction or Accepted: 26 July 2021 Published: 30 July 2021 discontinuation [4]. Resistance to cisplatin has been associated with multiple mechanisms, including Publisher’s Note: MDPI stays neutral alteration of target molecules, production of cisplatin-sequestering proteins, induction of with regard to jurisdictional claims in drug efflux pumps, upregulation of DNA repair pathways, and alterations in pro-survival published maps and institutional affil- and pro-apoptotic pathways [2,5]. Tumors may also possess multiple mechanisms of iations. resistance simultaneously [5]. Cisplatin exerts its antineoplastic activity primarily through the formation of DNA platination products; therefore, sensitivity of tumors to cisplatin greatly depends on the ability of tumor cells to recognize and repair cisplatin-induced DNA damage. In fact, there is strong evidence to show that the functionality of various DNA repair pathways significantly impacts tumor response to cisplatin treatment [6–10]. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Treatment toxicity is similarly mediated by, at least in part, DNA damage and the efficacy This article is an open access article of DNA repair pathways in normal tissues. distributed under the terms and Circumventing cisplatin resistance and toxicity remains a critical goal in enhancing the conditions of the Creative Commons therapeutic index of cisplatin and achieving sustained cancer control. Here, we summarize Attribution (CC BY) license (https:// the reported evidence from studies on the mechanism of DNA damage response and repair creativecommons.org/licenses/by/ in cisplatin-mediated cytotoxicity. We additionally discuss the DNA repair pathways and 4.0/). proteins implicated in cisplatin sensitivity and toxicity, as well as predictive markers for Int. J. Mol. Sci. 2021, 22, 8199. https://doi.org/10.3390/ijms22158199 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 5 of 5 Int. J. Mol. Sci. 2021, 22, 8199 2 of 18 pathways and proteins implicated in cisplatin sensitivity and toxicity, as well as predictive markers for cisplatin resistance. These biomarkers might allow for improved risk stratifi- cationcisplatin of patients resistance. and These selection biomarkers of more might individualized allow for improvedtreatment riskregimens. stratification Finally, of we pa- tients and selection of more individualized treatment regimens. Finally, we discuss current discuss current and future treatment strategies targeting DNA repair pathways that im- and future treatment strategies targeting DNA repair pathways that impact therapeutic pact therapeutic index of cisplatin treatment of cancers. index of cisplatin treatment of cancers. 2.2. Cisplatin Cisplatin Mechanism Mechanism of of Action Action in in Cancer Cancer Control Control and and Toxicity Toxicity DespiteDespite decades decades of of research research and and early early identi identificationfication of of DNA DNA as as the the primary primary cellular cellular targettarget of of cisplatin, cisplatin, the the mechanisms mechanisms involved involved in incisplatin cisplatin sensitivity sensitivity and and toxicity toxicity remain remain to beto befully fully elucidated. elucidated. Cisplatin’s Cisplatin’s antitumor antitumor activity activity begins begins with with cellular cellular uptake uptake through through coppercopper [11], [11], anion anion [12–14], [12–14 ],and and cation cation transporte transportersrs [15–18]. [15–18 It]. is It subsequently is subsequently aquated, aquated, al- 7 lowingallowing it to it tobind bind to tothe the guanine guanine N N position7 position on on DNA DNA [19]. [19]. By By doing doing so, so, cisplatin cisplatin generates generates DNADNA adducts adducts in in a ahighly highly conserved conserved manner. manner. The The most most common common of these of these adducts adducts are 1,2- are intrastrand1,2-intrastrand d (GpG) d (GpG) (between (between adjacent adjacent guanine guanine bases bases on on the the same same DNA DNA strand) strand) and and 1,2- 1,2- intrastrandintrastrand d (ApG)(ApG) (between (between adjacent adjacent adenine adenine and and guanine guanine bases bases on the on same the DNAsame strand)DNA strand)crosslinks. crosslinks. These adductsThese adducts distort distort the helical the helical structure structure of the DNAof the molecule,DNA molecule, disrupting dis- ruptingreplication replication and transcription and transcription [20–22 [20–22].]. Disruption Disruption of nuclear of nuclear DNA DNA is the is the most most studied stud- iedmechanism mechanism of cisplatin of cisplatin cytotoxicity; cytotoxicity; however, howe mitochondrialver, mitochondrial DNA DNA damage damage is also is indicated. also in- dicated.In fact, studiesIn fact, studies show that show cisplatin that cisplati bindsn tobinds both to nuclear both nuclea andr mitochondrial and mitochondrial DNA DNA with withthe samethe same affinity. affinity. Disruption Disruption of mitochondrial of mitochondrial DNA DNA replication replication and transcription and transcription leads leadsto mitochondrial to mitochondrial degradation degradation and apoptosis and apopto [2,sis23 ].[2,23]. In addition In addition to DNA to DNA damage, damage, cisplatin cis- platinbinds binds to cytoplasmic to cytoplasmic molecules, molecules, such assuch glutathione as glutathione (GSH) (GSH) and metallothionein and metallothionein (MT). (MT).Binding Binding of these of substratesthese substrates results inresults the generation in the generation of reactive of oxygen reactive species oxygen (ROS) species that (ROS)disrupt that mitochondrial disrupt mitochondrial membranes, membrane damage DNA,s, damage and eventually DNA, and induce eventually apoptosis induce [19] apoptosis(Figure1). [19] (Figure 1). FigureFigure 1. 1. MechanismsMechanisms of of cisplatin cisplatin therapeutic therapeutic ac action.tion. The The dark dark blue blue border border represents represents the the cell cell membrane, membrane, with with the the light light blueblue interior interior being being the the cytosol cytosol and and the the wh whiteite oval oval being being the the nucleus. nucleus. Cisplatin Cisplatin first first undergoes undergoes cellular cellular uptake uptake mediated mediated by by coppercopper transporters, transporters, indicated indicated by by the the cylindrical cylindrical structure structure crossi crossingng the the cell cell membrane. membrane. It It is is then then activated activated in in the the cytosol cytosol throughthrough aquation. aquation. Aquated Aquated cisplatin cisplatin induce inducess nuclear nuclear DNA DNA damage, damage, such such as the as theintr intrastrandastrand crosslinks crosslinks represented represented by the by redthe bar red linking bar linking two twoadjacent adjacent DNA DNA bases, bases, and andmitochondrial mitochondrial DNA DNA damage. damage. The activated The activated drug drugalso attacks also attacks reduced
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