Abstract
Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide. The limitations of cisplatin-based chemotherapy have prompted intense interest among scientists to search for alternative metal-based anticancer medicines. Gold(III) complexes have been among the most widely investigated since they showed higher cytotoxicity than cisplatin and promising in vitro and in vivo anticancer activities in CRC but their clinical usefulness has been limited by their poor stability under physiological conditions. A novel gold(III) porphyrin complexes [gold(III) porphyrin-adamantane chloride (SN1) and gold(III) porphyrin mono-acetate chloride (SN2)] with improved aqueous stability were synthesized. SN1 and SN2 reduced the survival of human CRC HT-29 and HCT-116 cell lines, caused cell cycle arrest in G2/M phase, and we observed downregulation of the expression of cyclin B1 and cyclin-dependent kinase 1 (Cdk1) along with up-regulation of the active form of p53, p21 and Bcl-2–associated X (Bax). Furthermore, SN1 and SN2 induced apoptosis by the intrinsic pathway, since they lead to the cleavage of caspase 9, caspase 3 and poly(ADP-ribose) polymerase (PARP), and up-regulating Bax. Phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), nuclear factor-κB (NF-κB) and extracellular signal-regulated kinases (ERK) are important for cell survival and proliferation. SN1 and SN2 lead to decrease in the activity of Akt where the phosphorylated form decreased with time as well as they caused an important decrease in the phosphorylation of ERK and activity of NF-κB. Finally, SN1 and SN2 complexes affected p38/mitogen-activated protein kinase (MAPK) pathway then we recorded an increase in the cyclooxygenase-2 expression and its enzymatic product prostaglandin E2.
Two gold(III) porphyrin complexes [gold(III) porphyrin-adamantane chloride (SN1) and gold(III) porphyrin mono-acetate chloride (SN2)] were synthetized and characterized. These two molecules have an antiproliferative effect on the colorectal cancer human HT-29 cells by leading the apoptosis. Indeed, numerous apoptotic markers of mitochondrial pathway are involved. [Display omitted]
•Gold(III) porphyrin-adamantane chloride (SN1) and -mono-acetate chloride (SN2) were made.•SN1 and SN2 reduced the survival of human colorectal cancer cell lines.•SN1 and SN2 induced apoptosis by the mitochondrial intrinsic pathway.•SN1 and SN2 lead to decrease signaling kinase survival pathways.•SN1 and SN2 caused an important decrease in activity of survival nuclear factor-κB.