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Kumar et al. Cancer Drug Resist 2019;2:161-77 I http://dx.doi.org/10.20517/cdr.2018.27 Page 165

Inside the cell, water replaces the Cl groups of cisplatin and generates reactive nucleophilic species. These
species have the ability to penetrate the nuclear membrane and can form covalent bond with the DNA
molecule (primarily guanine) which initiates the process of cell death. Activation of nucleotide excision
repair or other repair pathway introduces resistance in cancer cells. Prior to cisplatin entering in the nucleus,
[35]
glutathione conjugation with cisplatin by the enzyme GSH S-transferases reduces drug effectiveness .
Cisplatin interaction with the sulfhydryl-containing metallothioneins also diminishes drug efficacy.
Alternative pathway of cellular cisplatin resistance includes the efflux activity of the MRP2 (ABCC2)
[36]
transporter and ATP7B P-type adenosine triphosphatase (ATPase) transporter .

The EGFR/PI3K-PTEN/Akt/mTOR/ and Wnt/β-catenin signaling pathways play important roles in the
[37]
malignant transformation and drug resistance . These signaling pathways are frequently altered in various
cancers due to the anomalous expression levels of PTEN, HER2, EGFR1, and other tumor suppressor
gene/oncogenes. Some of the kinases involved in the cellular signaling also play a comprehensive role
[38]
in cancer development and drug resistance establishment . Due to its substantial implication in drug
resistance development, kinases are the second largest drug target family. In addition to this, tumor
microenvironment positively regulates these kinases and helps tumor to acquire resistance properties.
Several signaling pathways have been reported for their outstanding contribution to the maintenance of
tumor microenvironment. Mutation in EGFR and its downstream signaling leads to the expansion of cancer
[39]
cell population . Another transcription factor, polyoma enhancer activator 3 (Pea3) has been reported for
its pivotal engrossment in invasion and metastasis in small cell lung cancer. Vascular endothelial growth
factor stimulates angiogenesis and vasculogenesis (blood vessel formation) having potential to induce drug
resistance. Another well-known signaling molecule Wnt16B regulates important factor required for cell
[40]
proliferation and epithelial-mesenchymal transition in cancer cells . Nuclear factor-κB (NF-κB) regulates
the Wnt16B expression levels during these events. These pathways create a boundary and limit the drug
efficacy and lead to development of drug resistance. Additionally, malignant cells secrete plasminogen
activator inhibitor-1 which provides aggressiveness and facilitates cell proliferation . AKT and ERK1/2
[41]
signaling and reduced level of caspase 3 participate in these events [Figure 3].

GENETIC MODIFICATIONS IN DRUG RESISTANCE
DNA mutation
Variation in expression or mutation in the drug target proteins may be the major reason for drug resistance
initiation. Fluorodeoxyuridine monophosphate (FdUMP) actively targets thymidyate synthase . One of the
[42]
[43]
studies demonstrated that thymidyate synthase expression determines the 5-FU sensitivity . Thymidyate
synthase promoter polymorphism (TSER3/TSER3) negatively regulates 5-FU-based chemotherapy than the
[44]
heterozygous (TSER2/TSER3) /homozygous alternative polymorphism (TSER2/TSER2) . Overexpression
of thymidyate synthase encourages resistance to its inhibitors like TDX, 5-FU, and multi-targeted anti-
folate [45,46] . SN-38, a metabolite of CPT-11, inhibits DNA topoisomerase-I enzyme which relaxes super-
[47]
coiled double-stranded DNA during the replication process . Downregulation of topoisomerase-I
[48]
mRNA results in anti-sensitivity against CPT-11 in colorectal cancer . Anthracyclines (doxorubicin) and
epipodophyllotoxins (etoposide) are ideal target for the topoisomerase-II enzyme which also plays a vital
role during replication. Alteration in topoisomerase-II expression levels or mutation in this protein results in
resistant to doxorubicin/etoposide in colon cancer cells [49,50] .

Tubulin proteins such as α- and β-tubulin generate microtubule structures that maintain cell integrity,
[51]
regulates signaling/cell division and helps in vesicle transportation throughout the cellular compartments .
Tubulin polymerization/de-polymerization regulates appropriate spindle formation and chromosome
segregation during cell division. Taxanes (paclitaxel and docetaxel) and vinca alkaloids (vinblastine and
vincristine) repress the polymerization of tubulin which blocks cell division [52,53] . An in vitro study reported
that mutation in the β-tubulin proteins regulates the sensitivity against paclitaxel [54,55] .