Abstract
Cell-penetrating peptides (CPPs) are small peptide sequences used mainly as cellular delivery agents that are able to efficiently deliver cargo into cells. Some CPPs also demonstrate intrinsic anticancer properties. Previously, our group developed a new family of CPP2-thiazole conjugates that have been shown to effectively reduce the proliferation of different cancer cells. This work aimed to combine these CPP2-thiazole conjugates with paclitaxel (PTX) and 5-fluorouracil (5-FU) in PC-3 prostate and HT-29 colon cancer cells, respectively, to evaluate the cytotoxic effects of these combinations. We also combined these CPP2-thiazole conjugates with clotrimazole (CLZ), an antifungal agent that has been shown to decrease cancer cell proliferation. Cell viability was evaluated using MTT and SRB assays. Drug interaction was quantified using the Chou–Talalay method. We determined that CPP2 did not have significant activity in these cells and demonstrate that N-terminal modification of this peptide enhanced its anticancer activity in both cell lines. Our results also showed an uneven response between cell lines to the proposed combinations. PC-3 cells were more responsive to the combination of CPP2-thiazole conjugates with CLZ than PTX and were more sensitive to these combinations than HT-29 cells. In addition, the interaction of drugs resulted in more synergism in PC-3 cells. These results suggest that N-terminal modification of CPP2 results in the enhanced anticancer activity of the peptide and demonstrates the potential of CPPs as adjuvants in cancer therapy. These results also validate that CLZ has significant anticancer activity both alone and in combination and support the strategy of drug repurposing coupled to drug combination for prostate cancer therapy.
Highlights
Cell-penetrating peptides (CPPs) are one of the most promising vehicles for the delivery of various types of cargo and have been extensively studied for the transport of different substrates to cancer cells [1]
Our results have shown these conjugates have promising anticancer activity against these cancer cell lines [16]
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Summary
Cell-penetrating peptides (CPPs) are one of the most promising vehicles for the delivery of various types of cargo and have been extensively studied for the transport of different substrates to cancer cells [1]. CPPs are capable of transporting into the interior of living cells a wide variety of substrates such as drugs, peptides, proteins, liposomes, nanoparticles or even nucleic acids [3]. CPPs can be classified into three classes: cationic, amphipathic and hydrophobic [5]. More than 100 different CPPs are patented with approximately 83% being cationic [6]. Hydrophobic CPPs are still very scarce and represent approximately 15% of all discoveries to date [7]. These peptides are rapidly assimilated, the different classes exhibit distinct behaviours, especially concerning endocytic internalisation
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