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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 163

Figure 1. Mechanism of cisplatin resistance. Ligand binding to transforming growth factor beta (TGF-β) receptor initiates intracellular
signaling through Smad protein complex (SPC). In the nucleus, SPC bind with the DNA binding domain which results in expression of
p21/Waf1 and Nrf2 gene. p21/Waf1 and Nrf2 gene products tightly regulate glutathione metabolism. Cisplatin enters cells by passive
diffusion. At low chloride ion concentration, the chloride ion of cisplatin is replaced with water molecules and forms activated cisplatin
(aquation). Activated cisplatin enters the nucleus and results into the transcription of genes involved in anticancer activity. Glutathione
conjugation with cisplatin hinders its nuclear translocation and thereby its chemo-preventive potential resulting into cisplatin resistance

[18]
carcinoma during clinical trials . In addition to this, another MDR1 inhibitor zosuquidar in combination
[19]
with docetaxel did not show any effect in overall survival . These facts suggest that the ABC transporter
family comprise a high degree of functional redundancy.

Metabolism of chemotherapeutic drugs also possesses a major role in drug resistance initiation. Several studies
[20]
have shown that activation or inactivation of chemotherapeutic drugs leads to drug resistance. Meijer et al.
demonstrated that the thiol group of glutathione inactivates platinum-based chemotherapeutic drugs.
Absence or inactive form of the cellular enzyme that converts methotrexate and 5-fluorouracil (5-FU)
to their active forms are also responsible for drug resistance [21,22] . Thymidine phosphorylase converts
[23]
fluoropyrimidine prodrug (capecitabine) to 5-FU . Methylation of thymidine phosphorylase encoding
[24]
gene can cause capecitabine resistance . UDP glucuronosyltransferase 1 promoter methylation inactivates
its expression which positively regulates topoisomerase I inhibitor irinotecan drug and protects it’s from
deactivation [25,26] .

CELLILAR SIGNALING PATHWAYS IN DRUG RESISTANCE
The TGF-β pathway regulates numerous cellular processes including cellular growth and differentiation,
apoptosis and maintains cellular homeostasis . TGF-β plays an important role in the maintenance of
[27]
tumor microenvironment and its subsequent progression. Both intracellular and extracellular signals (DNA
damage and TGF-β) have potential to induce p21/Waf1 gene transcription. Oxidative stress also elevates
the p21/Waf1 and Nrf2 gene expression. Together, these proteins remarkably enhance the glutathione
metabolism and reduce the potential of the anticancer drug such as cisplatin [Figure 1].
[28]

The Cap’n’collar (CNC) family proteins play important role in gene transcription and mammalian
developmental process. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important member of CNC
family proteins . Nrf2 is a transcription factor known to modulate the expression of genes involved in the
[29]