Platinum-based drugs enter the cell via passive diffusion or active transport through copper transporters (CTRs), organic cation transporters (OCTs), and multidrug resistance proteins (MRPs). The reduction of the platinum-based drug accumulation in the cell due to these transporters can lead to platinum resistance.

Another method that causes resistance involves the deactivation of the platinum-based drugs through their binding with the detoxification components, glutathione (GSH) and metallothionein (MT).⁷

Furthermore, platinum resistance can occur due to an increased DNA repair process.

• the most common characteristic of platinum resistant cells.

• Nucleotide excision repair pathways recognize lesions in the DNA left by cisplatin adducts and proteins in repair systems may also recognize and remove cisplatin-induced lesions.¹⁹

• These cells also can have a higher threshold level for initiating apoptosis due to the overexpression of anti-apoptotic proteins or a malfunction in signaling by mitochondria.

  • For example, a mutation or loss of the tumor suppressor p53 can lead to the failure of apoptosis due to defective checkpoint responses.

• Lastly, platinum response is also negatively affected by the increase in the process of autophagy.⁷

On-Target Resistance

On-target resistance considers the resistance pathways taken when DNA adducts are formed with cisplatin.

• When cisplatin induces lesions on DNA, incisions are made on either side of the lesion.

• After inspecting for any damages to DNA integrity, the NER system repairs any damage to DNA.¹⁹

  • Expression of complementation group 1 (ERCC1), a pathway of excision repair, has been found to increase cisplatin resistivity. ²¹

    • studies have yet to confirm this observation as different results have been observed with differing types of cancer, requiring more research to be done to measure these claims¹⁹