A novel copper (II) complex activated both extrinsic and intrinsic apoptotic pathways in liver cancerous cells

Abstract

Recent advances have put fundamental focus on the application of copper (II) (Cu [II]) complexes as agents for fighting against cancer. To determine whether [Cu(L)(2imi)] complex as a novel Cu complex can induce apoptosis in HepG2 as cancerous cells and L929 as normal cells via extrinsic or intrinsic apoptotic pathways, both cell lines were treated for 24 and 48 hours at IC 50 concentrations of [Cu(L)(2imi)] complex. Then, the expression of some apoptosis-related genes including p53, caspase-8, bcl-2, and bax were assayed by real-time polymerase chain reaction. The [Cu(L)(2imi)] complex seems to inhibit the expression of bcl-2 in complex-treated HepG2 cancerous cells following the 24-and 48-hour treatment. The complex upregulated the p53, bax, and caspase-8 genes, therefore treatment of HepG2 cancerous cells with [Cu(L)(2imi)] complex induces programmed cell death via the upregulation of relative bax/bcl-2 ratio. Finally, this copper complex triggered apoptosis in HepG2 cells via both intrinsic and extrinsic pathway, whereas treatment of normal L929 cells with this complex induce apoptosis only via intrinsic pathway with the upregulation of relative bax/bcl-2 ratio and does not affect the expression level of caspase-8 gene and does not trigger the extrinsic pathway. Finally, these results obtained from present study confirm the role of a novel Cu complex on the induction of apoptosis process in HepG2 and L929 cells by overexpression of bax, inhibition of bcl-2 and increase of the relative bax/bcl-2 ratio. These results support that the [Cu(L)(2imi)] complex is able to induce apoptosis in cancerous cells, therefore, it has a potential for development as a novel anticancer drug. K E Y W O R D S bax, bcl-2, caspase-8, [Cu(L)(2imi)] complex, hepatocellular carcinoma, p53

Combinational treatment of all‐trans retinoic acid (ATRA) and bisdemethoxycurcumin (BDMC)‐induced apoptosis in liver cancer Hep3B cells

“…Therefore, based on these observations, ATRA combined with BDMC increased the ratio of Bak/Bcl-2 for leading to cell apoptosis. The Bax/Bcl-2 ratio was concerned with cell response to apoptotic signals (Rezaei et al, 2019).…”

A selective CuII complex with 4-fluorophenoxyacetic acid hydrazide and phenanthroline displays DNA-cleaving and pro-apoptotic properties in cancer cells

“…In order to find out whether complex 1 would be effective against a human tumor lineage, we used HeLa cells. Complex 1 proved to be a potent apoptosis inducer in tumor cells, as it was observed in many other copper complexes that exhibit this property 22 , 29 , 32 , 61 , 62 , which is the safest mechanism of action of a drug, since apoptosis is a controlled event 30 . The genomic DNA degradation event triggered by complex 1 is believed to be the responsible for the induction of apoptosis, as described by other authors 22 , 31 , 45 .…”

“…Generally, cells that suffer double- or single-strand breaks in DNA are paralyzed in the G0/G1 or G2 phases 60 . Several copper complexes exhibit the ability to degrade tumor cell DNA 22 , 61 , 62 , and such ability was detected in complex 1 . The damage on DNA is believed to be responsible for this cell cycle arrest.…”

Copper homeostasis dysregulation promoting cell damage and the association with liver diseases

“…Studies have shown that copper complexes can induce cell death by promoting DNA double-strand breaks. In the study by Rezaei et al , [ 74 ] Cu (II) complex was found to induce apoptosis in HEPG2 cells by up-regulating the expression of tumor suppressor gene P53 and apoptosis genes ( BAX and Caspase - 8 ) and down-regulating the expression of anti-apoptosis gene BCL-2 . Some novel copper complexes have also been developed for the photodynamic therapy (PDT) of HCC.…”