Loperamide, an FDA-Approved Antidiarrhea Drug, Effectively Reverses the Resistance of Multidrug Resistant MCF-7/MDR1 Human Breast Cancer Cells to Doxorubicin-Induced Cytotoxicity

Abstract

Loperamide is an FDA-approved antidiarrhea drug which acts on the μ-opioid receptors in the mesenteric plexus of large intestine and exhibits limited side effects. We hypothesized that loperamide might reverse the multidrug resistance (MDR) of human cancer cells to chemotherapeutic agents. MCF-7/MDR1 cells express high level of MDR1 and are resistant to doxorubicin. We found that loperamide significantly enhanced the cytotoxicity of doxorubicin to MCF-7/MDR1 cells in a dose-dependent manner. In conclusion, loperamide reversed the resistance of MCF-7/MDR1 cells to doxorubicin, suggesting that chemotherapy in combination with loperamide may benefit patients with MDR tumors once applied in clinic.

Association Between ABCB1 (MDR1) Gene Polymorphism and Unresponsiveness Combined Therapy in Chronic Hepatitis C virus

“…They also claimed that the infected patients by mutated virus showed increased incidence of HCC. Viral drug unresponsiveness is sometimes based on viral and/or bacterial gene recombinations, and resistance to the wide range of drugs (29, 40-42) but in general it is based on genomic variation and/or mutations of host organisms genome, intracellular functions and causes different tissue cancers in human (43-47). As claimed by Hoofnagle et al, the racial difference (variation in host genome) takes crucial role in the response to antiviral therapy (48).…”

“…The TT genotype of the same SNP in exon 26 of MDR1 gene causes over expression of gene activity, and effluxes many chemicals. Some recent reports insist that the TT alleles failed to efflux chemicals role, and cause to some types of cancer such as; HCC (30-32), breast (47), NSCLC (46), prostate (43), and ovarian cancers in human (44, 45). In conclusion, the homozygous TT alleles in MDR1 gene showed strong association with drug unresponsiveness in the current nonresponder patients with HCV who were treated by combined alpha 2a-interferon, and ribavirin for six months.…”

Cytotoxic Effects of Loperamide Hydrochloride on Canine Cancer Cells

“…Separate from its ability to inhibit proliferation and induce apoptosis, loperamide acts as a P-glycoprotein substrate [ 14 , 27 ]. Multidrug resistance of tumor cells is a significant problem in the use of cancer chemotherapy.…”

“…Multidrug resistance of tumor cells is a significant problem in the use of cancer chemotherapy. The classical mechanism of development involves P-glycoprotein over-expression [ 4 , 27 ]. Chemotherapy drugs kill many tumor cells, but may select for cells that overexpress P-glycoprotein; compounds that compete for P-glycoprotein, such as loperamide, may have the potential to enhance the efficacy of some anticancer agents [ 27 ].…”

“…The classical mechanism of development involves P-glycoprotein over-expression [ 4 , 27 ]. Chemotherapy drugs kill many tumor cells, but may select for cells that overexpress P-glycoprotein; compounds that compete for P-glycoprotein, such as loperamide, may have the potential to enhance the efficacy of some anticancer agents [ 27 ]. Indeed, a recent study found that loperamide was able to reverse multidrug resistance in a doxorubicin-resistant breast cancer cell line due to its high affinity binding to the efflux pump, leading to intracellular doxorubicin accumulation [ 27 ].…”