Table 2.

Overview of methods adopted by tumour cells for acquiring chemoresistance properties.

Chemoresistance method	Description	Key player genes, proteins and/or signalling pathways	References
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]
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]
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]
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]
DNA methylation mechanisms	Inhibition of key tumour suppressor genes leading to DNA methylations.	Caspase-8 promoter hypermethylation in neuroblastoma.	[38, 39]
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]
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]
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]