Reversal of Ovarian Cancer Cell Lines Multidrug Resistance Phenotype by the Association of Apiole with Chemotherapies

Abstract

Multidrug resistance (MDR) is the main obstacle in anticancer therapy. The use of drug combinations to circumvent tumor resistance is a well-established principle in the clinic. Among the therapeutic targets, glycoprotein-P (P-gp), an energy-dependent transmembrane efflux pump responsible for modulating MDR, is highlighted. Many pharmacological studies report the ability of calcium channel blockers to reverse tumor resistance to chemotherapy drugs. Isolated for the first time from parsley, the phenylpropanoid apiole is described as a potent calcium channel inhibitor. Taking this into account, herein, the ability of apiole to potentiate the action of well-established chemotherapeutics in the clinic, as well as the compound’s relationship with the reversal of the resistance phenomenon by blocking P-gp, is reported. The association of apiole with both chemotherapeutic drugs doxorubicin and vincristine resulted in synergistic effect, in a concentration-dependent manner, as evaluated by the concentration reduction index. Molecular docking analysis demonstrated the affinity between apiole and the active site of P-gp, corroborating the inhibitory effect. Moreover, apiole demonstrated druglikeness, according to ADME analysis. In conclusion, apiole possibly blocks the active P-gp site, with strong binding energy, which, in turn, inhibits doxorubicin and vincristine efflux, increasing the antiproliferative response of these chemotherapeutic agents.

Cytotoxic and Pro-Apoptotic Effects of a Sub-Toxic Concentration of Fluvastatin on OVCAR3 Ovarian Cancer Cells After its Optimized Formulation to Melittin Nano-Conjugates

“…The aim of the present work was to investigate the cytotoxic and pro-apoptotic efficacy of a sub-toxic concentration of FLV on human OVCAR3 ovarian cancer cells after its optimized formulation to MEL nano-conjugates. This specific cell line was selected because it represents an appropriate model system in which to study drug resistance ( Sakhare et al, 2014 ; Afonso de Lima et al, 2020 ) as well as the toxic potential of statins alone or in combination with other antineoplastic drugs against ovarian cancer ( Scoles et al, 2010 ; Casella et al, 2014 ; Abdullah et al, 2019 ; Yarmolinsky et al, 2020 ). A two-level, three-factor (2 3 ) full factorial design was employed for the preparation and optimization of FLV-MEL nano-conjugates.…”

Effects of Myristicin in Association with Chemotherapies on the Reversal of the Multidrug Resistance (MDR) Mechanism in Cancer

“…The interest in investigating the in vitro effects of the association between myristicin and chemotherapeutics in an ovarian tumor cell line resistant to multiple drugs arose from the results obtained and published by our group for the apiole molecule, which differs from myristicin only by the presence of one more methoxy group [ 8 ]. It is a phenylpropanoid found mainly in parsley (Apiaceae) and in species of the families Lauraceae and Piperaceae.…”

“…Apiole alone has no significant cytostatic effect on cell lines of resistant tumors. However, its association with the chemotherapy drugs vincristine and doxorubicin presented a synergistic effect, and this mechanism would be related to the affinity of the molecule to the active site of P-gp, antagonizing its action to promote drug efflux into the extracellular environment [ 8 ].…”

“…Although some studies have addressed the antiproliferative activity of myristicin, none of them investigated its potential mechanism of MDR reversal. Considering the similarity of the myristicin molecular structure with compound apiole recently studied by our research group ( Figure 1 ) and whose results indicated it is a potential reverser of MDR [ 8 ], the aim of this research was to investigate the effects of myristicin in association with chemotherapeutic agents in a multidrug-resistant cell line, as well as its binding affinity for P-gp efflux pump.…”

Synthesis, Selective Cytotoxic Activity against Human Breast Cancer MCF7 Cell Line and Molecular Docking of Some Chalcone-Dihydropyrimidone Hybrids

“…Compounds 9a and 9b presented lower IC50 values (6.4 and 14.5 µM, respectively) than the positive control doxorubicin (22.6 µM) for NCI/ADR-RES. This result is very relevant because this is an ovarian adenocarcinoma cell line that expresses the phenotype of resistance to multiple drugs, characterized by the high expression of glycoprotein-P (P-gp), an energy-dependent transmembrane efflux pump responsible for modulating multidrug resistance (MDR) [49]. Further studies with these molecules must be conducted on this cell line to investigate their role in MDR reversion.…”