A Low Dose of Aripiprazole Has the Strongest Sensitization Effect Among 19 Repositioned Bipolar Drugs in P-gp-overexpressing Drug-resistant Cancer Cells

Abstract

Background/Aim: We investigated drugs that could sensitize P-glycoprotein (P-gp)-overexpressing drug-resistant cancer cells to vincristine (VIC) or eribulin treatment and assessed their associated mechanisms of action. Materials and Methods: We investigated 15 bipolar drugs (quetiapine, risperidone, clozapine, asenapine, iloperidone, paliperidone, ziprasidone, trifluoperazine, loxapine succinate, pilocarpine, valproic acid, carbamazepine, levetiracetam, topiramate, and felbamate) to identify drugs with a sensitizing effect on VICresistant KBV20C cells at relatively low doses. Fluorescenceactivated cell sorting (FACS), annexin V analyses, and rhodamine uptake tests were performed to further investigate the mechanism of action. Results: We found that co-treatment with half the tested drugs (quetiapine, iloperidone, trifluoperazine, loxapine, risperidone, ziprasidone, or felbamate) at low doses could highly sensitize VIC-resistant KBV20C cells. With lower amounts of the bipolar drugs or VIC, we found that among the 15 bipolar drugs tested, 2 combinations (VIC-quetiapine and VIC-trifluoperazine) had much higher sensitization effects, suggesting that lower effective doses were sufficient for sensitizing P-gp-overexpressing resistant cells compared to those required with the other drugs. Furthermore, when we compared quetiapine and trifluoperazine to previously known bipolar drugs (fluphenazine, thioridazine, pimozide, or aripiprazole), we found that aripiprazole, administered at lower doses, had a much higher sensitization effect. We also demonstrated that co-treatment with another anti-mitotic drug (eribulin) increased the sensitization of KBV20C cells similar to VIC. We also found that aripiprazole had higher P-gp-inhibitory activity than the other bipolar drugs, indicating that this activity was involved in the higher level of VIC-aripiprazole sensitization. Conclusion: Co-treatment of anti-mitotic drug-resistant cancer cells with a low dose of aripiprazole had the strongest sensitization effect and is highly dependent on P-gp-inhibitory activity.

PKM2 Is Overexpressed in Glioma Tissues, and Its Inhibition Highly Increases Late Apoptosis in U87MG Cells With Low-density Specificity

“…Microscopic observations were performed as previously described (19)(20)(21), in order to examine the effect of shikonin, compound 3K, or vincristine on cellular growth. Briefly, U87MG cells with 30-40% confluence were treated with 5 nM vincristine or 2 μM shikonin for 1 or 2 days.…”

“…Fluorescence-activated cell sorting analysis. Fluorescenceactivated cell sorting analysis was performed as previously described (19)(20)(21), in order to determine whether PKM2 inhibitors led to cell-cycle arrest. Briefly, cells with 30-40% confluence were treated with 2 μM shikonin, 15 μM compound 3K, or 5 nM vincristine for 24 h. The cells were then treated with trypsin and collected by centrifugation.…”

“…in vivo 36: 694-703 (2022) Annexin V analysis. Annexin V analysis was performed using an annexin V-fluorescein isothiocyanate staining kit (BD Bioscience, Franklin, NJ, USA) as previously described (19)(20)(21), in order to measure apoptosis quantitatively. Briefly, cells with 30-40% confluence were treated with 2 μM shikonin, 15 μM compound 3K, or 5 nM vincristine for 24 h. The cells were then treated with trypsin and collected by centrifugation.…”

Repurposing Antipsychotics for Cancer Treatment

“…The authors also reported a significant reduction of the anti-apoptotic protein survivin as well as inhibition of P-gp pumps, both leading to reduced cells’ resistance to chemotherapeutic agents [ 147 ]. In the context of P-gp pumps, two additional in vitro studies supported that the effective P-gp inhibition by ARP increased the potency of anti-mitotic drugs when these two drugs were combined [ 148 , 149 ]. Finally, Kim et al, using cell culture (in vitro) and xenografted mice (in vivo), supported that ARP induced apoptosis-mediated cytotoxicity and migration suppression by direct inhibition of Src oncogenic tyrosine and therefore inhibition of the signaling cascade molecules (phosphorylated phosphatidylinositide 3-kinase, STAT3, and Akt), all involved in glioma progression [ 150 ].…”

Drug Repositioning With an Anticancer Effect: Contributions to Reduced Cancer Incidence in Susceptible Individuals

“…Considering that mutations in the membranerelated receptors or kinases are correlated with cancer growth, it is assumed that drugs that target these cellular membrane receptors may also possess anticancer effects. Drugs used for the treatment of bipolar disorders that can be repositioned include fluphenazine, thioridazine, pimozide, aripiprazole, and valproic acid (23)(24)(25)(26)(27). As these drugs have anticancer effects, several clinical trials have been conducted to test their efficacy in various types of solid tumors, as well as in combination with other chemotherapeutic drug therapies.…”