Table 1.
Intracellular regulators of cisplatin resistance with clinical implication.
| Regulator | Action Mechanism | Relevance to CDDP Resistance | Reference |
|---|---|---|---|
| Cellular uptake | |||
| CTR1 | Membrane copper transporter | 1. Low expression levels in CDDP-resistant cancer cells. 2. Correlation between CTR1 expression levels and intracellular platinum concentration. 3. Copper chelators enhance CDDP efficacy in vitro and in vivo. 4. Low expression levels in tumors predict poor clinical efficacy of CDDP. |
[16,17,18,19,20,21] |
| CTR2 | Membrane copper transporter | 1. The induction of CTR1 cleavage. 2. High expression levels in tumors predict poor clinical efficacy of CDDP. |
[22,23,24] |
| OCT2 | Organic cation transporter | Low expression levels in tumors predict poor clinical efficacy of CDDP. | [25] |
| Cellular export | |||
| ATP7A/ATP7B | Copper-exporting P-type ATPase | 1. High expression levels in CDDP-resistant cancer cells. 2. High expression levels in tumors predict poor clinical efficacy of CDDP. |
[21,26,27,28,29] |
| MRP2 | ATP-binding cassette multidrug transporter | 1. High expression levels in CDDP-resistant cancer cells. 2. High expression levels in tumors predict poor clinical efficacy of CDDP. |
[30,31,32] |
| Drug inactivation | |||
| GSH | Intracellular electrophiles scavenger | 1. High expression levels in CDDP-resistant cancer cells. 2. High expression levels in tumors predict poor clinical efficacy of CDDP. |
[33,34,35] |
| Metallothionein | Detoxification enzyme of a heavy metal | 1. High expression levels in CDDP-resistant cancer cells. 2. High expression levels in tumors predict poor clinical efficacy of CDDP. |
[36,37] |
| DNA damage repair | |||
| ERCC1 | NER | 1. High expression levels in CDDP-resistant cancer cells. 2. High expression levels in tumors predict poor clinical efficacy of CDDP. |
[38,39,40,41,42,43,44,45] |
| XPF | NER | 1. High expression levels in CDDP-resistant cancer cells. 2. High expression levels in tumors predict poor clinical efficacy of CDDP. |
[46] |
| BRCA1/BRCA2 | HR | BRCA1/2-mutated tumors correlate to good responders to CDDP. | [47,48] |
CDDP: cisplatin, CTR1: copper transporter 1, CTR2: copper transporter 2, OCT2: organic cation transporter 2, ATP7A: copper-transporting ATPase 1, ATP7B: copper-transporting ATPase 2, ERCC1: DNA excision repair protein ERCC-1, XPF: DNA repair endonuclease XPF, BRCA1: breast cancer type 1 susceptibility protein, BRCA2: breast cancer type 2 susceptibility protein, MRP: multidrug resistance-associated protein, GSH: glutathione, NER: nucleotide excision repair, HR: homologous recombination.