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Chemoresistance method | Description | Key player genes, proteins and/or signalling pathways | References |
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Drug efflux mechanisms | Utilisation of drug efflux active pump proteins for expulsion of multiple cytotoxics from tumour cell cytoplasm, thus inducing multidrug resistance (MDR). | ATP-dependent binding cassette (ABC) transporter proteins, multidrug resistance 1 (MDR1) gene, P-glycoprotein (P-gp), multidrug resistance 1 protein (MRP1), ABCG2. | [23–26] |
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Drug modulation | Tumour cell ability to inactivate, or at least attenuate, drug activation through the modulation of expression of key enzyme/s involved in the target cytotoxic drug’s pharmacological and pharmacokinetic pathways. | Decreased expression or impairment of folylpoly-gamma glutamate-synthetase activity, resulting in antifolate drug resistance. Effect of glutathione on cisplatin inactivation-mediated chemoresistance. | [27–29] |
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Modification of drug targets | Upregulated expression or amplification of a target protein/enzyme, which may prove crucial for drug potency and effectiveness. | β-catenin, thymidylate synthase. | [30, 31] |
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Repair mechanisms following DNA damage | Exacerbated activity of components of the nucleotide excision repair pathway following tumour cell DNA damage. | Excision repair cross complementing 1 protein, microsatellite instability phenotype due to mutations in DNA mismatch repair genes. | [32–37] |
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DNA methylation mechanisms | Inhibition of key tumour suppressor genes leading to DNA methylations. | Caspase-8 promoter hypermethylation in neuroblastoma. | [38, 39] |
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p53 status | Dysfunction or loss of DNA damage/other stress induced p53 pathway-mediated apoptotic activity. | Mouse double minute 2 (Mdm2), p53 encoding gene (TP53). | [40–46] |
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Apoptotic pathway defects | Dysfunction or inactivation of the cytotoxic drug targeted intrinsic/extrinsic proapoptotic pathways in tumour cells. | Bcl-2 protein family, cellular FADD-like interleukin 1 beta converting enzyme-inhibitory protein (c-FLIP), cellular inhibitors of apoptosis proteins (cIAPs). | [47–59] |
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Proliferative pathway activation | Stimulation of cell proliferation through modulation of the PI3K and extracellular signal-regulated kinase (ERK) survival signalling pathways | Protein tyrosine kinases (PTKs) families, epidermal growth factor receptor (EGFR) family, transcription factor kappa B (NFκB), Sirtuins (SIRTs). | [60–68] |
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