Revisiting the Anti-Cancer Toxicity of Clinically Approved Platinating Derivatives

Abstract

Cisplatin (CDDP), carboplatin (CP), and oxaliplatin (OXP) are three platinating agents clinically approved worldwide for use against a variety of cancers. They are canonically known as DNA damage inducers; however, that is only one of their mechanisms of cytotoxicity. CDDP mediates its effects through DNA damage-induced transcription inhibition and apoptotic signalling. In addition, CDDP targets the endoplasmic reticulum (ER) to induce ER stress, the mitochondria via mitochondrial DNA damage leading to ROS production, and the plasma membrane and cytoskeletal components. CP acts in a similar fashion to CDDP by inducing DNA damage, mitochondrial damage, and ER stress. Additionally, CP is also able to upregulate micro-RNA activity, enhancing intrinsic apoptosis. OXP, on the other hand, at first induces damage to all the same targets as CDDP and CP, yet it is also capable of inducing immunogenic cell death via ER stress and can decrease ribosome biogenesis through its nucleolar effects. In this comprehensive review, we provide detailed mechanisms of action for the three platinating agents, going beyond their nuclear effects to include their cytoplasmic impact within cancer cells. In addition, we cover their current clinical use and limitations, including side effects and mechanisms of resistance.

Keywords: DNA damage; ER stress response; carboplatin; cellular uptake; chemoresistance; cisplatin; clinical usages; immunogenic cell death; influx and efflux pumps; interstrand and intrastrand DNA crosslinks; mechanisms of action; non-nuclear targets; oxaliplatin; ribosome biogenesis; transcription regulation.

Figure 1

Structural formula of cisplatin. The molecule was adapted from the structure published in the CheBI database [13] using ChemDraw software (v21.0.0.28), PerkinElmer, Waltham, MA, USA.

Figure 2

CDDP targets the nucleus, mitochondria, ER, plasma membrane, and cytoskeleton to induce cell death in its role as an anti-cancer drug. CDDP enters the cell via passive diffusion and high affinity copper uptake protein 1 (CTR1) and is removed from the cell by efflux transporters, ATP7A, ATP7B, and multidrug resistance protein 2 (MRP2). (A) CDDP forms intrastrand and interstrand crosslinks, distorting the DNA helix, inhibiting transcription (represented by the red cross) and activating p53-mediated apoptosis. (B) CDDP damages mitochondrial DNA (mtDNA), preventing transcription of electron transport chain (ETC) genes. Impaired ETC function results in ROS formation that further damages the mitochondria and activates the intrinsic and extrinsic apoptotic pathways. (C) CDDP induces the ER stress via the unfolded protein response (UPR), marked by upregulation of GRP78 and PERK-phosphorylation of eIF2α; ATF4 and CHOP are activated leading to ER-induced apoptosis. ER stress also leads to a release of calcium into the cytoplasm, which can directly activate caspase-12 and -4, as well as calpains, leading to apoptosis. High levels of calcium are also taken up by the mitochondria, depolarizing the membrane, resulting in apoptosis via cytochrome C release. (D) CDDP increases membrane fluidity and induces aggregation of components of the death inducing signalling complex (DISC) in the plasma membrane, resulting in extrinsic apoptotic activation. (E) CDDP activates acid sphingomyelinase (aSMase) which leads to cytoskeletal collapse and production of ceramides, signalling cell death. Created with BioRender.com (accessed on 11 November 2022).

Figure 3

Mechanisms of transcription inhibition by CDDP. (A) CDDP hinders transcription by sequestering transcription factors away from promoter regions. (B) Bulky CDDP lesions act as a physical roadblock to transcription machinery, preventing transcript elongation. (C) CDDP interstrand crosslinks hinders nucleosome mobility, preventing chromatin remodelling and maintaining condensed chromatin that prevents transcription. Red crosses represent inhibition of transcription. Created with BioRender.com (Accessed on 11 November 2022).

Figure 4

Structural formula of carboplatin. The molecule was adapted from the structure published in the CheBI database [13] using ChemDraw software (v21.0.0.28), PerkinElmer, Waltham, MA, USA.

Figure 5

CP targets the nucleus, the mitochondria and ER to induce cell death in its role as an anti-cancer drug. CP enters the cell via passive diffusion and high affinity copper uptake protein 1 (CTR1) and is removed from the cell by efflux transporters, ATP7A, ATP7B, and multidrug resistance protein 2 (MRP2). (A) CP forms DNA adducts, intrastrand or interstrand crosslinks, which result in deformation of the DNA helix; transcription inhibition, represented by the red cross, results in replication errors, leading to elevated p53 activity, subsequently activating the apoptosis pathway. (B) CP upregulates micro-RNA 145 (miRNA-145) expression, a tumour-suppressor, leading to p53 activation; subsequently p53-mediated mitochondrial-induced apoptosis is triggered. (C) CP causes a production of reactive oxygen species (ROS), leading to ER stress, marked by an upregulation of GRP78 and PERK-mediated phosphorylation of eIF2α; ATF4 and CHOP are activated leading to ER-induced apoptosis. (D) ER stress also leads to a release of calcium into the cytoplasm, which can directly activate caspase-12 and lead to apoptosis; high levels of calcium are taken up by the mitochondria, depolarizing the membrane. Cytochrome C (Cyt C) and apoptosis-inducing factor (AIF) are released into the cytoplasm, where Cyt C is able to activate caspase-9 and cause mitochondrial-induced apoptosis. AIF also promotes ROS production to further the cycle. (E) DNA damage leads to elevated PARP levels, inducing AIF translocation to the nucleus; the combination of both results in PARP-mediated cell death (parthanatos). Created with BioRender.com (Accessed on 11 November, 2022).

Figure 6

Structural formula of oxaliplatin. The molecule was adapted from the structure published in the CheBI database [13] using ChemDraw software (v21.0.0.28), PerkinElmer, Waltham, MA, USA.

Figure 7

OXP targets the nucleus in two ways, the mitochondria and ER to induce cell death in its role as an anti-cancer drug. OXP enters the cell via passive diffusion and High affinity copper uptake protein 1 (CTR1) and is removed from the cell by efflux transporters, ATP7A, ATP7B, and multidrug resistance protein 2 (MRP2). (A) OXP forms DNA adducts, intrastrand or interstrand crosslinks, which result in deformation of the DNA helix; transcription inhibition (represented by a red cross) results in transcription and replication errors, leading to elevated p53 activity, subsequently activating the apoptosis pathway. (B) OXP induces nucleophosmin (NPM1) translocation from the nucleolus to the nucleoplasm; this process causes nucleolar segregation, inhibition of RNA Polymerase I (RNA Pol I) activity and formation of fibrillarin caps. RNA Pol I is also inhibited by DNA damage blocking the phosphorylated S484 isoform of UBF1. Subsequently, ribosomal DNA (rDNA) transcription is inhibited (represented by a red cross), and ribosome biogenesis is inhibited. Translation is thus inhibited. (C) OXP induces reactive oxygen species (ROS) production leading to the activation of pro-apoptotic factors, Bax and Bak, in a nuclear-independent fashion that leads to caspase-9 activation and subsequent mitochondrial-induced apoptosis. (D) ROS production by OXP causes sufficient ER stress to begin apoptosis; during early-apoptosis calreticulin (CRT) and ERp57 translocate to the plasma membrane and act as “find-me” and “eat-me” signals to nearby immune cells; during early-to-late apoptosis and late-apoptosis, ATP and high-grade mobility box 1 (HMGB1), respectively, are secreted into the extracellular environment. ATP acts as another “find-me” signal to monocytes, macrophages and other immune cells, while HMGB1 can bind to TLR4 on dendritic cells to instigate a full immune response. Created with BioRender.com (11 November, 2022).

Figure 8

OXP targets the nucleolus and induces nucleolar stress and segregation, and inhibition of ribosome biogenesis. (A) OXP induces the translocation of nucleophosmin (NPM1) from the nucleolus to nucleoplasm. (B) Pre-ribosomal subunit transport to the nucleoplasm is inhibited by the lack of NPM1. (C) Inhibition of rDNA transcription (represented by a red cross) by RNA polymerase I (Pol I) occurs after NPM1 translocation (D) OXP-induced DNA crosslinks phosphorylate upstream binding factor 1 (UBF1), preventing RNA polymerase I-mediated rDNA transcription. (E) Separation of the fibrillar center and granular component results in segregation of the fibrillarin center along the periphery of the nucleolus, forming nucleolar caps. (F) All the effects of OXP in the nucleolus prevent ribosome biogenesis, and subsequently translation inhibition (represented by a red cross). Created with BioRender.com (Accessed on 11 November, 2022).