Abstract
Copper complexes are promising anticancer agents widely studied to overcome tumor resistance to metal-based anticancer drugs. Nevertheless, copper complexes per se encounter drug resistance from time to time. Adenosine-5′-triphosphate (ATP)-responsive nanoparticles containing a copper complex CTND and B-cell lymphoma 2 (Bcl-2) small interfering RNA (siRNA) were constructed to cope with the resistance of cancer cells to the complex. CTND and siRNA can be released from the nanoparticles in cancer cells upon reacting with intracellular ATP. The resistance of B16F10 melanoma cells to CTND was terminated by silencing the cellular Bcl-2 gene via RNA interference, and the therapeutic efficacy was significantly enhanced. The nanoparticles triggered a cellular autophagy that amplified the apoptotic signals, thus revealing a novel mechanism for antagonizing the resistance of copper complexes. In view of the extensive association of Bcl-2 protein with cancer resistance to chemotherapeutics, this strategy may be universally applicable for overcoming the ubiquitous drug resistance to metallodrugs.
Highlights
Metal-based anticancer drugs represented by cisplatin are the main chemotherapeutics; the clinical use of these drugs is largely limited by dose-limiting side effects and drug resistance.[1]
Results and discussion small interfering RNA (siRNA) and chemotherapeutics into cells,[9] which would colocalize them in tumor regions with the same pharmacokinetic pro les to modulate the drug resistance
It has been shown that co-delivery of siRNA and cisplatin prodrug by NPs could enhance the tumor cell response to the drug.[9]
Summary
Studied its antitumor activity and mechanism of action.[4]. CTB is more cytotoxic than cisplatin against various tumor cells and especially the cisplatin-resistant ones. CTN encountered drug resistance this time in B16F10 melanoma cells (Fig. S1A†), with its inhibition activity being signi cantly lower than that of CTB. Speci c small interfering RNA (siRNA) can target and silence nearly any gene of interest, including genes encoding proteins involved in the acquisition of multidrug resistance.[7] We have veri ed this by adding Bcl-2 siRNA to the CTN-treated B16F10 cells, which markedly enhanced the antiproliferative activity of CTN (Fig. S1C†). CTND (Fig. 1) derived from CTN was used as a tumorinsensitive model copper complex to test the applicability of the siRNA-strategy in overcoming tumor resistance. A variety of experiments proved that this method is an effective approachh to conquer the Bcl-2regulated drug resistance to metallodrugs
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