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Page 162 Kumar et al. Cancer Drug Resist 2019;2:161-77 I http://dx.doi.org/10.20517/cdr.2018.27

to these drugs and they often experience severe adverse effects such as neutropenia, diarrhea and potential
hair loss. The major reason for this effect remains indiscriminate targeting of both normal and malignant
cells by these chemotherapeutic agents. More than 200 anticancer drugs including cytotoxic and biologically
[3]
targeted agents are currently in use having a low success rate of ~5% in the clinical application . Therefore,
identification of novel drug targets and development of effective chemotherapeutic agents to overcome
drug resistance in cancer remains a major priority. Based on tumor response to the initial therapy, chemo-
resistance mechanisms are classified into two categories including de novo (intrinsic) and acquired
(extrinsic), however, the detailed mechanism(s) of chemo-resistance in human cancers remains to be
understood completely.

Previous studies have identified drug efflux transporters/multi drug resistance pumps, uridine diphospho-
glucuronosyltransferase (UGT) superfamily, cytochrome P450s and Glutathione S-transferases (GSTs)
as some classical drug resistance target(s) in cancer chemotherapy [4-6] . GSTs includes eukaryotic and
prokaryotic phase II family isozyme. For the detoxification process, GST catalyzes the reduced form of
glutathione (GSH) to xenobiotic substrates. GST expression levels are linked with higher tumor drug
resistance. Another GST specific isoenzyme called Glutathione S-transferases P are ubiquitous in nature
[7]
and showed elevated levels in non-drug resistant and drug-resistant cancers . ATP-binding cassette (ABC)
transporters are the membrane-bound proteins require ATP for functioning. These transporters allow the
substrates in (influx) or out (efflux) of the cells. Higher expression of ABC transporter also results in efflux
of cytotoxic agent from the cancer cells which leads to drug resistance. In addition to above mechanisms of
drug resistance, mutation-induced alterations in cytochrome P450 activity or other types of modifications in
malignant cells including glycosylation of anticancer agents by UGT superfamily may modify drug efficacy
[8]
as a result of altered drug metabolism .
More recent studies have identified abrupt cellular signaling pathways as underlying mechanisms for
the development of cancer drug resistance. Some key process involve in drug resistance include tumor
heterogeneity, reactivation of drug targets, hyperactivation of alternative pathways, cross-talk with the
microenvironment, altered DNA response and its repair, modification in epigenetic pathways, impairment in
[9]
apoptosis/autophagy and existence of cancer stem cells . Any alteration in these pathways initially initiates
changes in metabolic pathways and alteration in endocrine system functioning with later association with
uncontrolled cell division through gene regulation. Innovations in molecular and biochemical techniques
led to the identification/establishment of some new pathways including transforming growth factor beta
(TGF-β) and Keap1-Nrf2 and some emerging drug resistance targets such as FOXO3A, FOXM1, FAKs,
ANXA2, KCNN3, MIEN1 and epigenetic modifiers such as miRNAs and alternative splicing. In the present
review we discussed these novel anticancer drug resistant targets and pathways.

DRUG TRANSPORT AND METABOLISM
Various trans-membranous proteins such as ABC have been well reported for the resistance initiation
against several chemotherapeutic drugs. These include P-glycoprotein known as multi-drug resistance
protein 1 (MDR1), ABCC1 known as MDR-associated protein 1 (MRP1) and ABCG2 known as breast cancer
resistance protein (BCRP). These transporter proteins are highly specific to eliminate cancer therapeutic
drugs such as topoisomerase inhibitors, taxanes, and antimetabolites. Epithelial cells which participate in the
[10]
excretion process express higher levels of MDR1 proteins . Several studies demonstrate that overexpression
of MDR1 in different cancers such as colorectal, hepatocellular, renal, breast, lung, prostate, lymphomas
and leukemia’s have been tightly associated with chemo-resistance [11-14] . Breast cancer resistance protein also
possess chemo-resistive properties against leukemia [15,16] . Some cancer therapeutic drugs such as nilotinib,
[17]
erlotinib, sunitinib, and imatinib are prime target for MDR1 and BCRP efflux pumps . MDR1 pump
inhibitor, tariquidar in combination with anthracycline/taxanes showed partial activity in stage III/IV breast