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Open AccessArticle

Potentiation of Low-Dose Doxorubicin Cytotoxicity by Affecting P-Glycoprotein through Caryophyllane Sesquiterpenes in HepG2 Cells: an in Vitro and in Silico Study

1
Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
2
Department of Medicinal Chemistry, Faculty of Pharmacy, Mazandaran University of Medical Sciences, 48175-866 Sari, Iran
3
Department of Biochemical Science “A. Rossi Fanelli”, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
4
Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(2), 633; https://doi.org/10.3390/ijms21020633
Received: 17 December 2019 / Revised: 9 January 2020 / Accepted: 16 January 2020 / Published: 17 January 2020
Doxorubicin represents a valuable choice for different cancers, although the severe side effects occurring at the high effective dose limits its clinical use. In the present study, potential strategies to potentiate low-dose doxorubicin efficacy, including a metronomic schedule, characterized by a short and repeated exposure to the anticancer drug, and the combination with the natural chemosensitizing sesquiterpenes β-caryophyllene and β-caryophyllene oxide, were assessed in human hepatoma HepG2 cells. The involvement of P-glycoprotein (P-gp) in the HepG2–chemosensitization to doxorubicin was evaluated. Also, the direct interaction of caryophyllene sesquiterpenes with P-gp was characterized by molecular docking and dynamic simulation studies. A metronomic schedule allowed us to enhance the low-dose doxorubicin cytotoxicity and the combination with caryophyllane sesquiterpenes further potentiated this effect. Also, an increased intracellular accumulation of doxorubicin and rhodamine 123 induced by caryophyllane sesquiterpenes was found, thus suggesting their interference with P-gp function. A lowered expression of P-gp induced by the combinations, with respect to doxorubicin alone, was observed too. Docking studies found that the binding site of caryophyllane sesquiterpene was next to the ATP binding domain of P-gp and that β-caryophyllene possessed the stronger binding affinity and higher inhibition potential calculated by MM-PBSA. Present findings strengthen our hypothesis about the potential chemosensitizing power of caryophyllane sesquiterpenes and suggest that combining a chemosensitizer and a metronomic schedule can represent a suitable strategy to overcome drawbacks of doxorubicin chemotherapy while exploiting its powerful activity. View Full-Text
Keywords: β-caryophyllene; β-caryophyllene oxide; metronomic treatment; doxorubicin; liver cancer; multidrug resistance; computational chemistry; MDR1 (multidrug resistance-1) inhibition; Structure activity relationship; Active site prediction β-caryophyllene; β-caryophyllene oxide; metronomic treatment; doxorubicin; liver cancer; multidrug resistance; computational chemistry; MDR1 (multidrug resistance-1) inhibition; Structure activity relationship; Active site prediction
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Di Sotto, A.; Irannejad, H.; Eufemi, M.; Mancinelli, R.; Abete, L.; Mammola, C.L.; Altieri, F.; Mazzanti, G.; Di Giacomo, S. Potentiation of Low-Dose Doxorubicin Cytotoxicity by Affecting P-Glycoprotein through Caryophyllane Sesquiterpenes in HepG2 Cells: an in Vitro and in Silico Study. Int. J. Mol. Sci. 2020, 21, 633.

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