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The mechanism of cisplatin follows four steps:
(1) cellular uptake
(2) aquation/activation
(3) DNA platination
(4) cellular processing of platinum-DNA lesions
Figure 4. General Mechanism of Cisplatin6
(1) Cellular Uptake
The uptake of platinum agents is conducted through two methods: passive diffusion and active transport. The small size and planar structure of cisplatin allows for it to passively diffuse through the plasma membrane. However, active transport via copper transporters, specifically CTR1 and CTR2 have been shown to play a major role in the mediation of the influx of cisplatin into the cell.5,6
(2) Aquation / Activation
The square planar shape of cisplatin allows for ligand substitution to occur. Compared to the bloodstream, the chloride concentration in the cytoplasm is much lower (4-10 mM). This leads to water molecules replacing the chloride ligands in cisplatin yielding [Pt(NH3)2Cl(H2O)]+ and [Pt(NH3)2(H2O)2]2+. The substitution of the chloride ligands for water molecules results in a positive charge on cisplatin, and this is known as aquation/activation.5,6
Figure 5. Aquation of Cisplatin32
Figure 6. How Cisplatin Attaches Itself to DNA Stands.32
Figure 7. Different formations of platinum-DNA adducts.6
(3) DNA platination
The positively charged aquated/activated cisplatin enables the attraction of cisplatin to the negatively charged DNA in the nucleus. DNA is the primary target of platinum-based anticancer therapies. The third step, DNA platination results when the aquated/activated cisplatin reacts with the nucleophilic N7 sites of the guanine bases to form platinum-DNA adducts. This creates interstrand or intrastrand crosslinks.6 Different types of adducts are shown in Figure 7. The 1,2- intrastrand cross-link is the most common type. Cross-linking prevents the cell from undergoing DNA replication.7
(4) Cellular processing of platinum-DNA lesions
The lesions in the DNA cause the cell to stop at the G2/M phases of the cell cycle in order to try and repair the platinum-DNA lesions.6 The inhibition of transcription can also occur when RNA polymerase stops at the cross-link when transcribing the DNA and calls for a transcription-coupled repair machinery that will try and repair the lesion. If the damage can not be fixed, the cell will initiate apoptosis by releasing excess reactive oxygen species (ROS) from the mitochondria.5
Apoptosis occurs extrinsically and intrinsically through a variety of pathways. For example, in the extrinsic pathway as shown in Figure 8 tumor necrosis factor (TNF) binds with the receptors of the tumor necrosis factor receptor superfamily. This initiates a self-activation of caspase-8 to induce apoptosis. Apoptosis can also occur intrinsically as shown in Figure 9 through proapoptotic signaling where the mitochondria signals for cytochrome c to release, inducing a caspase cascade to cause apoptosis.7
Figure 8. Extrinsic Pathway of Apoptosis. 8
Figure 9. Intrinsic Pathway of Apoptosis.9
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