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

Carolina Afonso De Lima,Stanley Nunes Siqueira Vasconcelos,João Ernesto De Carvalho,Juliana Mozer Sciani,Giovanna Barbarini Longato,Ana Lúcia Tasca Gois Ruiz,Ian Lucas De Souza Bueno,Mary Ann Foglio

doi:10.3390/ph13100327

Carolina Afonso De Lima, Stanley Nunes Siqueira Vasconcelos + Show 6 more

Open Access

https://doi.org/10.3390/ph13100327

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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.

Highlights

Including more than 100 different diseases, cancer is characterized by disordered cells growth with the ability to invade tissues and organs; some types of tumor cells can spread to other body parts in a process called metastasis [1]
Considering that calcium channel blockers have been shown to be substrates for P-gp and potent Multidrug resistance (MDR) reversers [16], this study aimed to evaluate the action of apiole in adjuvant treatment with well-established chemotherapy drugs used in the clinic, such as doxorubicin and vincristine, on ovarian tumor cell lines
The nuclear magnetic resonance (NMR) spectral data (Table 1) obtained for isolated compound was in accordance to previously reported data [17], confirming the structure (Figure 1)

Summary

Introduction

Including more than 100 different diseases, cancer is characterized by disordered cells growth with the ability to invade tissues and organs; some types of tumor cells can spread to other body parts in a process called metastasis [1]. Multidrug resistance (MDR) is one of the main obstacles of anticancer treatment and believed to cause treatment failure in over 90% of patients with metastatic cancer [2]. One of the major causes of multidrug resistance is the enhanced efflux of drugs by membrane ABC (ATP-binding cassete) transporters. Targeting ABC transporters projects a promising approach to eliminating or suppressing drug resistance in cancer treatment [4]. Among these members, P-glycoprotein (P-gp, referred to as multidrug resistance protein 1, MDR1, or ABCB1) is the best characterized efflux pump that mediates cancer MDR [5]

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