Multidrug Resistance of Cancer Cells and the Vital Role of P-Glycoprotein

Abstract

P-glycoprotein (P-gp) is a major factor in the multidrug resistance phenotype in cancer cells. P-gp is a protein that regulates the ATP-dependent efflux of a wide range of anticancer medicines and confers resistance. Due to its wide specificity, several attempts have been made to block the action of P-gp to restore the efficacy of anticancer drugs. The major goal has been to create molecules that either compete with anticancer medicines for transport or function as a direct P-gp inhibitor. Despite significant in vitro success, there are presently no drugs available in the clinic that can “block” P-gp–mediated resistance. Toxicity, unfavourable pharmacological interactions, and a variety of pharmacokinetic difficulties might all be the reason for the failure. On the other hand, P-gp has a significant effect in the body. It protects the vital organs from the entry of foreign bodies and other toxic chemicals. Hence, the inhibitors of P-gp should not hinder its action in the normal cells. To develop an effective inhibitor of P-gp, thorough background knowledge is needed in this field. The main aim of this review article was to set forth the merits and demerits of the action of P-gp on cancer cells as well as on normal cells. The influence of P-gp on cancer drug delivery and the contribution of P-gp to activating drug resistance were also mentioned.

Combination of Antimalarial and CNS Drugs with Antineoplastic Agents in MCF-7 Breast and HT-29 Colon Cancer Cells: Biosafety Evaluation and Mechanism of Action

“…Many types of cancer overexpress Pgp which prevents cancer drugs from reaching their cellular targets [ 36 ]. Antineoplastic drugs that interfere with the DNA replication process, such as doxorubicin, are especially vulnerable to P-gp overactivity [ 37 ]. On the other hand, novel drugs that inhibit P-gp can be promising agents for cancer cell growth inhibition and overcoming multidrug resistance [ 37 ].…”

“…Antineoplastic drugs that interfere with the DNA replication process, such as doxorubicin, are especially vulnerable to P-gp overactivity [ 37 ]. On the other hand, novel drugs that inhibit P-gp can be promising agents for cancer cell growth inhibition and overcoming multidrug resistance [ 37 ]. Ras, c-Raf, p53, and other oncogenes are reported to affect the regulation of P-gp expression [ 38 ].…”

Dihydropyrimidine Dehydrogenase-Mediated Resistance to 5-Fluorouracil: Mechanistic Investigation and Solution

“…About 60–90% of its administered dose gets metabolized in liver and extrahepatic tissues, while 10–20% get excreted unchanged in urine; thus, only a small amount of 5-FU remains to exert its anticancer activity by inhibiting TS. In addition to this, 5-FU has to withstand one more challenge, i.e., the metabolism of 5-FU to inactive metabolite due to DPD overexpression in tumor tissues before cytotoxic nucleotides can be formed. , This type of inactivation belongs to one of the pharmacokinetic resistance mechanisms . DPD catalyzes the first step of pyrimidine degradation, i.e., nicotinamide adenine dinucleotide phosphate (NADPH) dependent reduction of thymine and uracil moieties of drug molecules.…”

“…6,7 This type of inactivation belongs to one of the pharmacokinetic resistance mechanisms. 8 DPD catalyzes the first step of pyrimidine degradation, i.e., nicotinamide adenine dinucleotide phosphate (NADPH) dependent reduction of thymine and uracil moieties of drug molecules. Cancer cells like TE-5R (human esophageal squamous carcinoma cells (ESCC) with overexpressed DPD) are 15.6 times more resistant to 5-FU chemotherapy as compared to wild type cells.…”

5-Fluorouracil and Curcumin Combination Coated with Pectin and Its Strategy towards Titanium Dioxide, Dimethylhydrazine Colorectal Cancer Model with the Evaluation of the Blood Parameters

“…5-FU is the first line chemotherapeutic agent used for the treatment of CRC in both palliative and adjuvant situations. Over the last four decades, various techniques have been developed and used to increase the anti-tumor [ 10 ] effectiveness of 5-FU and overcome clinical resistance, including the use of 5-FU-based combination regimens and 5-FU pro-drugs [ 11 ]. More than 80% of 5-FU is catabolized by hepatic dihydropyrimidine dehydrogenase (DPD), while the remaining causes cell death by blocking RNA and DNA synthesis via fluorodeoxyuridine monophosphate (FdUMP) and fluouridine triphosphate (FUTP) [ 12 ].…”