Overcoming vincristine resistance in cancer: Computational design and discovery of piperine‐inspired P‐glycoprotein inhibitors

Abstract

P-glycoprotein (P-gp)/MDR-1 plays a major role in the development of multidrug resistance (MDR) by pumping the chemotherapeutic drugs out of the cancer cells and reducing their efficacy. A number of P-gp inhibitors were reported to reverse the MDR when co-administered with chemotherapeutic drugs. Unfortunately, none has approved for clinical use due to toxicity issues. Some of the P-gp inhibitors tested in the clinics are reported to have cross-reactivity with CYP450 drug-metabolizing enzymes, resulting in unpredictable pharmacokinetics and toxicity of co-administered chemotherapeutic drugs. In this study, two piperine analogs (3 and 4) having lower cross-reactivity with CYP3A4 drug-metabolizing enzyme are identified as P-glycoprotein (P-gp) inhibitors through computational design, followed by synthesis and testing in MDR cancer cell lines over-expressing P-gp (KB Ch R 8-5, SW480-VCR, and HCT-15). Both the analogs significantly increased the vincristine efficacy in MDR cancer cell lines at low micromole concentrations. Specifically, 3 caused complete reversal of vincristine resistance in KB Ch R 8-5 cells and found to act as competitive inhibitor of P-gp as well as potentiated the vincristine-induced NF-KBmediated apoptosis. Therefore, 3 ((2E,4E)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-(4-hydroxy-3-methoxyphenyl)penta-2,4-dien-1-one) can serve as a potential P-gp inhibitor for in vivo investigations, to reverse multidrug resistance in cancer. 52 | SYED Et al. 1 | INTRODUCTION P-glycoprotein (P-gp/MDR-1) belonging to the ABC family of efflux pump transporters plays an important role in the development of drug resistance in cancer (Ghaleb et al., 2018; Waghray & Zhang, 2018). From the clinical studies, it is evident that the expression of MDR-1 is inversely proportional to the efficacy of first-line chemotherapy (Chung, Santiago, De Jesus, Trinidad, & See, 2016). Moreover, some of the clinical studies have also revealed an increased expression of P-gp after chemotherapy, which positively correlates with the relapse of the tumor (Chevillard et al., 1996; Zhou,

Vincristine in Combination Therapy of Cancer: Emerging Trends in Clinics

“…These compounds mostly comprise inhibitors of P-glycoprotein (P-gp) efflux pumps, which can sensitize resistant cells to the correspondent drugs. Vincristine belongs to the drugs, which are efficiently transported from cells via P-gp, and in some cancer cell types overexpressing this efflux pump, leads to strong resistance to vincristine treatment [ 175 ]. The group of Chen et al presented a series of seco-based compounds derived from a previously reported compound praeruptorin A, which potently reverses P-gp-based multidrug resistance.…”

“…Another example of a P-gp inhibitor, synergizing with vincristine, has been presented by Syed et al, who computationally designed, synthesized, and evaluated two piperine analogs, one of which was proven to potentiate vincristine anticancer activity. This compound was able to reduce vincristine IC 50 in resistant KB cells 24-fold while being inactive in non-resistant cells [ 175 ]. Not only synthetic products but also compounds from natural sources have anti-P-gp activity and were tested in combination with vincristine.…”

Patchouli alcohol induces G0/G1 cell cycle arrest and apoptosis in vincristine‐resistant non‐small cell lung cancer through ROS‐mediated DNA damage

“…44,45 Studies have indicated that targeting P-gp or CSCs is a strategy for the treatment of drug-resistant cancer cells. 15,43 Our results showed that A549/V16 cells had higher expression of P-gp, CD44, and CD133 than A549 cells, suggesting that drug pumping out and CSCs characteristics cause the development of VCR resistance in NSCLC cells. However, PA treatment reduced the expression of these proteins in both cell lines, especially in A549/V16 cells.…”

“…Studies have shown that P‐gp overexpression and stemness phenotype are related to resistance to chemotherapy drugs against cancer 15,16 . To determine the effects of PA on drug resistance, the expression of P‐gp and CSCs markers (CD44, CD133, and EpCAM) in PA‐treated cells was detected using immunofluorescence staining and western blotting.…”

“…There is increasing evidence that ABCB1/p‐glycoprotein (P‐gp), ABCC1/multidrug resistance‐associated protein 1, and ABCG2/breast cancer resistance protein enhance resistance to vinca alkaloids in human cancers 14 . P‐gp is overexpressed in NSCLC cells and efficiently transports VCR from cells, leading to strong resistance to VCR treatment 15 . In addition, several studies have shown that the characteristics of cancer stem cells (CSCs) are related to tumor recurrence, invasion, and drug resistance 16 .…”