Molecular mechanisms of cisplatin resistance in cervical cancer

Figures & data

Figure 1 Molecular mechanisms of CPR in cervical cancer.

Notes: The molecular mechanisms underlying cisplatin resistance in cervical cancer are complex and associated with the following features: 1) reduction in the intracellular accumulation of the platinum compounds (decrease in uptake, increase in efflux, and increased drug detoxification by cellular thiols); 2) increase in DNA damage repair (increased NER, loss of MMR, and increased TLS); 3) inactivation of apoptosis; 4) activation of EMT; 5) alteration in DNA methylation, microRNA profile, cancer stem cell characteristics, and expression of stress-response chaperones.
Abbreviations: CPR, cisplatin resistance; CTR1, copper transporter 1; EMT, epithelial–mesenchymal transition; ERCC1, excision repair cross-complementing; GSH, glutathione; HSC71, heat-shock cognate protein 71; HSP, heat-shock protein; MMR, mismatch repair; MRP1, multidrug resistance protein 1; MSH2, MutS homolog 2; MTs, metallothioneins; NER, nucleotide excision repair; NF-κB, nuclear factor-κB; OCT3, organic cation transporter 3; P-gp, P-glycoprotein; PMS2, post-meiotic segregation 2; TLS, translesion synthesis.

Figure 2 Inactivation of apoptosis pathway and CPR in cervical cancer.

Note: Multiple molecules and signaling pathways that inhibit apoptosis can lead to CPR.
Abbreviations: CPR, cisplatin resistance; MAPK, mitogen-activated protein kinases; NF-κB, nuclear factor-κB; TNFAIP8, tumor-necrosis-factor-α-induced protein 8.

Table 1 Agents to overcome CPR in cervical cancer

Compound	Type of study	Mode of action	References
Genistein	In vitro	Inhibition of NF-κB and Akt/mTOR pathways	Sahin et al^Citation93
Curcumin	In vitro	Modulation of multidrug-resistant proteins such as MRP1 and P-gp1	Roy and Mukherjee^Citation16
Tea polyphenols	In vitro	Induction of apoptosis	Singh et al^Citation94
Melatonin	In vitro	Induction of apoptosis	Pariente et al^Citation95
Mifepristone	In vitro, in vivo	Inducing apoptosis, increasing cisplatin, accumulating and upregulating p53	Segovia et al^Citation96 Jurado et al^Citation97 Li and Ye^Citation98
Epigallocatechin gallate	In vitro	Regulating NF-κB p65, COX-2, p-Akt, and p-mTOR pathways	Kilic et al^Citation100
Ursolic acid	In vitro	Inhibiting NF-κB activation	Li et al^Citation101
Morinda citrifolia	In vitro	Altering oxidative stress marker and antioxidant activity, inducing apoptosis	Gupta and Singh^Citation102 Gupta et al^Citation103
Wogonin	In vitro	Accumulation of intracellular reactive oxygen species and induced apoptosis	He et al^Citation104
Pyrrolidine dithiocarbamate	In vitro	Blocking cisplatin-induced activation of NF-κB, enhancing apoptosis	Zheng et al^Citation59

Abbreviations: CPR, cisplatin resistance; MRP1, multidrug resistance protein 1; NF-κB, nuclear factor-κB; P-gp1, P-glycoprotein 1.

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