Cariprazine, A Dopamine D2/D3 Receptor Partial Agonist, Modulates ABCG2-Mediated Multidrug Resistance in Cancer

Abstract

Multidrug resistance (MDR) is a continuing clinical problem that limits the efficacy of chemotherapy in cancer. The over expression of the ATP-binding cassette (ABC) family G2 (ABCG2) transporter is one of the main mechanisms that mediates MDR in cancer. Molecular modeling data indicated that cariprazine, a dopamine D2/D3 receptor partial agonist, had a significant binding affinity for ABCG2 transporter with a Glide XP score of −6.515. Therefore, in this in vitro study, we determined the effect of cariprazine on MDR resulting from the overexpression of ABCG2 transporters. Alone, cariprazine, at concentrations up to 20 μM, did not significantly decrease cell viability. Cariprazine, at concentrations ranging from 1 to 10 μM, did not significantly alter the cytotoxicity of mitoxantrone (MX) in the parental non-small cell cancer cell line, H460 and colon cancer cell S1. However, cariprazine (1–20 μM) significantly enhanced the efficacy of ABCG2 substrate antineoplastic drug MX in the ABCG2-overexpressing MDR cell line, H460-MX20 and S1M1-80, by reducing the resistance fold from 28 to 1 and from 93 to 1.33, respectively. Cariprazine, in a concentration-dependent (1–20 μM), significantly increased the intracellular accumulation of Rhodamine 123 in S1M1-80. Interestingly, 10 or 20 μM of cariprazine significantly decreased the expression levels of the ABCG2 protein in the colon and lung cancer cell lines, suggesting that cariprazine inhibits both the function and expression of ABCG2 transporters at nontoxic concentrations. Overall, our results suggest that cariprazine, via several distinct mechanisms, can resensitize resistant cancer cells to mitoxantrone.

Novel 3-((2-chloroquinolin-3-yl)methylene)indolin-2-one derivatives produce anticancer efficacy in ovarian cancer in vitro

“…The cells were further incubated with MTT for 4 hrs to produce the formation of the purple formazan crystals, which is indicative of viable cells. DMSO was added to dissolve the crystals and the absorbance was determined at 570 nm wavelength as described previously [26]. The IC 50 was calculated and the selectivity of the compounds was determined by comparing survival in normal cells.…”

“…The survival of ovarian cancer cells (A2780) in the presence of LM08 was further determined by colony formation assay as previously described in detail [26,27,28]. Briefly, A2780 cells were incubated with vehicle (0 μM) or LM08 (10 or 20 μM) for 24 hrs.…”

Repurposing Antipsychotics for Cancer Treatment

“…In another study, cariprazine, a D3-preferring D3/D2 receptor partial agonist used for the treatment of schizophrenia and bipolar disorder [ 160 ], was utilized in vitro in ABCG2-mediated multidrug-resistant non-small lung cancer (H460-MX20 cell line) and colon cancer cell line (S1M1-80). The authors reported that cariprazine synergistically enhanced the efficacy of the antineoplastic drug mitoxantrone by downregulating the expression of ABCG2 protein, with the exact molecular mechanism of this modulation remaining unknown [ 161 ].…”

Cancer and the Dopamine D2Receptor: A Pharmacological Perspective

“…Likewise, ABCG2-mediated chemoresistance in MDR cells is reduced by 10 mM D 3 antagonists PG01037, NGB 2904, SB27 7011A, and U99194 (Hussein et al, 2017). Hussein et al (2018) later reported that cariprazine (which they termed a D 2 /D 3 partial agonist) had similar effects and suggested it might be repurposed for cancer chemotherapy. The concentrations required, however, were $1 mM, much higher than found clinically with maximal doses of the cariprazine, a drug that also has active metabolites that accumulate at even higher levels (Nakamura et al, 2016).…”