Curcumin-loaded nanoparticles induce apoptotic cell death through regulation of the function of MDR1 and reactive oxygen species in cisplatin-resistant CAR human oral cancer cells

Abstract

Curcumin is a polyphenolic compound which possesses anticancer potential. It has been shown to induce cell death in a variety of cancer cells, however, its effect on CAL27‑cisplatin-resistant human oral cancer cells (CAR cells) has not been elucidated to date. The low water solubility of curcumin which leads to poor bioavailability, however, has been highlighted as a major limiting factor. In this study, we utilized water-soluble PLGA curcumin nanoparticles (Cur-NPs), and investigated the effects of Cur-NPs on CAR cells. The results showed Cur-NPs induced apoptosis in CAR cells but exhibited low cytotoxicity to normal human gingival fibroblasts (HGFs) and normal human oral keratinocytes (OKs). Cur-NPs triggered DNA concentration, fragmentation and subsequent apoptosis. Compared to untreated CAR cells, a more detectable amount of Calcein-AM accumulation was found inside the treated CAR cells. Cur-NPs suppressed the protein and mRNA expression levels of MDR1. Both the activity and the expression levels of caspase-3 and caspase-9 were elevated in the treated CAR cells. The Cur-NP-triggered apoptosis was blocked by specific inhibitors of pan-caspase (z-VAD-fmk), caspase-3 (z-DEVD-fmk), caspase-9 (z-LEHD-fmk) and antioxidant agent (N-acetylcysteine; NAC). Cur-NPs increased reactive oxygen species (ROS) production, upregulated the protein expression levels of cleaved caspase-3/caspase-9, cytochrome c, Apaf-1, AIF, Bax and downregulated the protein levels of Bcl-2. Our results suggest that Cur-NPs triggered the intrinsic apoptotic pathway through regulating the function of multiple drug resistance protein 1 (MDR1) and the production of reactive oxygen species (ROS) in CAR cells. Cur-NPs could be potentially efficacious in the treatment of cisplatin-resistant human oral cancer.

Nanomedicine therapeutic approaches to overcome cancer drug resistance

“…This has been shown for α-tocopheryl PEG1000 succinate [129,130] and poly[bis(2-hydroxylethyl)-disulfide-diacrylate-β-tetraethylenepentamine]-polycaprolactone copolymer [131] for the inhibition of efflux-dependent mechanisms or carbon nanotubes for membrane permeabilization and sensitization to photo thermal therapy [132]. Drug efflux systems [129-131,133-136], resistance due to presence of CSC [132,137-139], DNA damage/repair [136,140-142], apoptosis signaling pathways [139,141,143], resistance against radiation therapy [136,139,141,142], and resistance against thermal treatment [142] are being studied in vitro and in vivo as targets for nanomedicines in order to develop the best treatment regimens. Diverse functions and multiple effects are typical for the composition and design of multifunctional nanomedicines.…”

In Vitro and in Vivo Antitumoral Effects of Combinations of Polyphenols, or Polyphenols and Anticancer Drugs: Perspectives on Cancer Treatment

“…Chang et al found that CUR-loaded nanoparticles (Cur-NPs) selectively reduced the viability of cisplatin-resistant CAL-27 human oral cancer cells (CAR cells) in a dose- and time-dependent manner. Cur-NPs induced intrinsic apoptotic processes (up-regulating Bax, capsase-3, and caspase-9 synthesis and down-regulating expression of multiple drug resistance protein 1 (MDR1) and Bcl-2) and enhanced ROS production in CAR cells [152]. …”

Polyphenols delivery by polymeric materials: challenges in cancer treatment

“…The most of the proposed delivery nano-systems show mechanisms of action mirror that of free curcumin, allowing an effective passive targeting on different cancer cells, including cervical (Das et al, 2010), oral (Chang et al, 2013a), prostate (Mukerjee & Vishwanatha, 2009;Sanoj Rejinold et al, 2011), breast (Sanoj Rejinold et al, 2011 cancers, osteosarcoma (Peng et al, 2014), melanoma (Mangalathillam et al, 2012), and medulloblastoma (Altunbas et al, 2011) by controlling the CUR release over time. Furthermore, in vivo studies proved that nanoparticles prepared by free radical polymerization of N-isopropylacrylamide (NIPAAm), N-vinyl-2-pyrrolidone (VP), and poly(ethylene glycol) acrylate (PEG-mA), proposed for the treatment of pancreatic cancer, show negligible toxicity in mouse model (Bisht et al, 2007), while the emulsion polymerization of butyl-cyanoacrylate in the presence of CT allows the obtainment of a CUR delivery vehicles suitable for the treatment of hepatic cancer with favorable pharmacokinetic profiles (Duan et al, 2010).…”