Abstract
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.
Highlights
Multidrug resistance (MDR), i.e., a cross-resistance to a broad variety of anticancer drugs unrelated to structure and activity, produces chemotherapy failure and tumor progression [1]
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
Preliminary experiments showed that blank solid lipid nanoparticles (SLNs), i.e., SLNs without CURC, did not increase the release of lactate dehydrogenase (LDH) after 24 h in MDA-MB-231 cells if the nano-carriers were diluted at 1:100 in the culture medium (Figure S2)
Summary
Multidrug resistance (MDR), i.e., a cross-resistance to a broad variety of anticancer drugs unrelated to structure and activity, produces chemotherapy failure and tumor progression [1]. One of the most studied mechanisms of MDR is the overexpression of drug efflux pumps belonging to the adenosine triphosphate (ATP) Binding Cassette (ABC) transporters family, characterized by a broad and overlapping spectrum of substrates [2,3]. The main ABC transporters clinically associated with the development of MDR are P-glycoprotein (Pgp/ABCB1), MDR Related Proteins (MRPs/ABCCs), and Breast Cancer Resistance Protein (BCRP/ABCG2) [4,5]. Chemotherapy based on anthracyclines, such as doxorubicin, and taxanes are the main treatment options for patients with TNBC. The onset of drug resistance due to the presence of Pgp reduces the efficacy of neoadjuvant and adjuvant chemotherapy in many cases [8,9]. Improving the success rate of anthracycline-based chemotherapy in TNBC is still an unmet need
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