Curcumin-Loaded Solid Lipid Nanoparticles Bypass P-Glycoprotein Mediated Doxorubicin Resistance in Triple Negative Breast Cancer Cells
Gamal-Eldein Fathy Abd-Ellatef,
Elena Gazzano,
Daniela Chirio,
Ahmed Ragab Hamed,
Dimas Carolina Belisario,
Carlo Zuddas,
Elena Peira,
Barbara Rolando,
Joanna Kopecka,
Mohamed Assem Said Marie,
Simona Sapino,
Sohair Ramadan Fahmy,
Marina Gallarate,
Abdel-Hamid Zaki Abdel-Hamid,
Chiara Riganti
Affiliations
Gamal-Eldein Fathy Abd-Ellatef
Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy
Elena Gazzano
Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy
Daniela Chirio
Department of Drug Science and Technology, University of Torino, via P. Giuria 9, 10125 Torino, Italy
Ahmed Ragab Hamed
Chemistry of Medicinal Plants Department, Biology Unit, Central Laboratory of Pharmaceutical and Drug Industries Research Division, National Research Centre, 33 El Bohouth St., Dokki, Giza 12622, Egypt
Dimas Carolina Belisario
Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy
Carlo Zuddas
Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy
Elena Peira
Department of Drug Science and Technology, University of Torino, via P. Giuria 9, 10125 Torino, Italy
Barbara Rolando
Department of Drug Science and Technology, University of Torino, via P. Giuria 9, 10125 Torino, Italy
Joanna Kopecka
Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy
Mohamed Assem Said Marie
Zoology Department, Faculty of Science, Cairo University, Gamaa Street, Dokki, Giza 12622, Egypt
Simona Sapino
Department of Drug Science and Technology, University of Torino, via P. Giuria 9, 10125 Torino, Italy
Sohair Ramadan Fahmy
Zoology Department, Faculty of Science, Cairo University, Gamaa Street, Dokki, Giza 12622, Egypt
Marina Gallarate
Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, 33 El Bohouth St., Dokki, Giza 12622, Egypt
Abdel-Hamid Zaki Abdel-Hamid
Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, 33 El Bohouth St., Dokki, Giza 12622, Egypt
Chiara Riganti
Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy
Multidrug resistance (MDR) is a critical hindrance to the success of cancer chemotherapy. The main thing responsible for MDR phenotypes are plasma-membranes associated with adenosine triphosphate (ATP) Binding Cassette (ABC) drug efflux transporters, such as the P-glycoprotein (Pgp) transporter that has the broadest spectrum of substrates. Curcumin (CURC) is a Pgp inhibitor, but it is poorly soluble and bioavailable. To overcome these limitations, we validated the efficacy and safety of CURC, loaded in biocompatible solid lipid nanoparticles (SLNs), with or without chitosan coating, with the goal of increasing the stability, homogeneous water dispersibility, and cellular uptake. Both CURC-loaded SLNs were 5−10-fold more effective than free CURC in increasing the intracellular retention and toxicity of doxorubicin in Pgp-expressing triple negative breast cancer (TNBC). The effect was due to the decrease of intracellular reactive oxygen species, consequent inhibition of the Akt/IKKα-β/NF-kB axis, and reduced transcriptional activation of the Pgp promoter by p65/p50 NF-kB. CURC-loaded SLNs also effectively rescued the sensitivity to doxorubicin against drug-resistant TNBC tumors, without signs of systemic toxicity. These results suggest that the combination therapy, based on CURC-loaded SLNs and doxorubicin, is an effective and safe approach to overcome the Pgp-mediated chemoresistance in TNBC.
