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Differential Effects of Dopamine D3 Receptor Antagonists in Modulating ABCG2 -Mediated Multidrug Resistance (MDR)

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2017, Master of Science in Pharmaceutical Science (MSP), University of Toledo, Pharmaceutical Sciences (Pharmacology/Toxicology).
The G2 subfamily of the ATP-binding cassette transporters (ABCG2), also known as the breast cancer resistance protein (BRCP), is an efflux transporter that plays an important role in protecting the cells against endogenous and exogenous toxic substances. The ABCG2 transporters are also highly expressed in the blood-brain barrier (BBB), providing protection against specific toxic compounds. Unfortunately, their overexpression in cancer cells results in the development of multi-drug resistance (MDR), and thus, chemotherapy failure. Dopamine3 receptor (D3R) antagonists were shown to have excellent anti-addiction properties in preclinical animal models but produced limited clinical success with the lead molecule. Thus, other more potent D3R antagonists, notably NGB2904, SB-277011A, and U99194, and PG01037 were dropped from further studies. Whether ABCG2 transporters limited D3R antagonists’ efficacy or whether these D3R antagonists could modulate ABCG2-mediated MDR has not been evaluated before. The present study was designed a) in a quest to understand whether ABCG2 transporters might be a limiting factor in D3R antagonists’ accumulation in the brain; b) if these D3R antagonists could be repurposed as anticancer chemo adjuvants to reverse MDR mediated by ABCG2 transporters. Interestingly, the structure of various D3R antagonists is similar to that of substrates for the ABCG2 transporter. We found that the D3R antagonists (PG01037, NGB2904, SB-277011A, and U99194), alone up to 50µM, do not produce significant toxicity towards normal or cancer cells. In contrast, the D3R antagonists (PG010037, NGB2904, SB-277011A, and U99194) significantly sensitized ABCG2 overexpressing HEK293/ABCG2; H460/MX-20, S1-M1-80 and A549-MX-10 cells to well-known anticancer agent’s mitoxantrone (MX) and doxorubicin (DOX) that are substrates of ABCG2 transporters. As shown by accumulation and efflux assay D3R antagonists combination enhanced accumulation of in MX in ABCG2 overexpressing H460-MX20 cells. Additionally, D3R antagonists (PG01037 and NGB2904) at a concentration of only 5µM significantly downregulated the expression of ABCG2 when incubated for 24 and 48 hours with ABCG2 overexpressing cells, suggesting that D3R antagonists reverse ABCG2 mediated drug resistance by not only inhibiting its function but also downregulating its expression. Furthermore, D3R antagonists were found to produce synergistic anticancer activity when combined with MX and DOX. In conclusion, this is the first study to show the interaction of D3R antagonists with ABCG2 transporters suggesting that D3R antagonists might be ABCG2 substrates, and combining D3R antagonists with certain anticancer agents that are substrates of ABCG2 transporters (i.e. MX and DOX) could produce beneficial results in ABCG2 overexpressing MDR cancer cells.
Amit Tiwari (Committee Chair)
Frank Hall (Committee Member)
Zahoor Shah (Committee Member)
98 p.

Recommended Citations

Citations

  • Hussein, N. A. (2017). Differential Effects of Dopamine D3 Receptor Antagonists in Modulating ABCG2 -Mediated Multidrug Resistance (MDR) [Master's thesis, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1492537484118157

    APA Style (7th edition)

  • Hussein, Noor. Differential Effects of Dopamine D3 Receptor Antagonists in Modulating ABCG2 -Mediated Multidrug Resistance (MDR). 2017. University of Toledo, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1492537484118157.

    MLA Style (8th edition)

  • Hussein, Noor. "Differential Effects of Dopamine D3 Receptor Antagonists in Modulating ABCG2 -Mediated Multidrug Resistance (MDR)." Master's thesis, University of Toledo, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=mco1492537484118157

    Chicago Manual of Style (17th edition)