Abstract. Liver cancer is a malignant tumour with high morbidity and fatality rates that is common worldwide. At present, the clinical approaches to treating primary liver cancer include partial hepatectomy, systemic or local chemotherapy, radiotherapy, radiofrequency ablative surgery and liver transplantation. However, all of these approaches have shortcomings, including poor prognosis and numerous side-effects. A large number of studies have proven that many effective ingredients in traditional Chinese medicine, particularly the flavonoid compounds extracted from plants, have achieved breakthroughs in terms of enhancing the effects and reducing the toxicity of chemotherapy and radiotherapy, preventing tumour metastasis and relapse after surgery, alleviating the clinical symptoms of advanced tumours, improving the quality of life of the patient with tumours and extending patient long-term survival. The purpose of the present study was to investigate the impact of isoquercitrin, the flavonoid from Bidens bipinnata L. extract, on the progression of liver cancer and to achieve a deeper understanding of the biological characteristics of isoquercitrin's involvement in the progression of liver cancer. In the in vitro experiments, isoquercitrin was found to strongly inhibit the proliferation of human liver cancer cells, promote the apoptosis of human liver cancer cells, and block the cell cycle in the G1 phase. Isoquercitrin activated caspase-3, -8 and -9, inhibited the expression level of ERK and p38MAPK protein phosphorylation, and promoted the phosphorylation of JNK. Additionally, isoquercitrin reduced the expression level of PKC in human liver cancer cells. In the in vivo experiments, isoquercitrin was also found to significantly inhibit the growth of transplanted tumours in nude mice. The present study confirmed that isoquercitrin could inhibit the progression of human liver cancer in vivo and in vitro, and the molecular mechanism of isoquercitrin may be closely associated with the MAPK and PKC signalling pathways.

To develop potential next-generation metal anticancer agents, we designed and synthesised five Cu(II) 2-pyridine-thiosemicarbazone complexes by modifying the hydrogen atom at the N-4 position of ligands, and then investigated their structure-activity relationships and anticancer mechanisms. Modification of the N-4 position with different groups caused significant differences in cellular uptake and produced superior antitumor activity. Cu complexes arrested the cell cycle at S phase, leading to down-regulation of levels of cyclin and cyclin-dependent kinases and up-regulation of expression of cyclin-dependent kinase inhibitors. Cu complexes exerted chemotherapeutic effects via activating p53 and inducing production of reactive oxygen species to regulate expression of the B-cell lymphoma-2 family of proteins, causing a change in the mitochondrial membrane potential and release of cytochrome c to form a dimer with apoptosis protease activating factor-1, resulting in activation of caspase-9/3 to induce apoptosis. In addition, Cu complexes inhibited telomerase by down-regulating the c-myc regulator gene and expression of the human telomerase reverse transcriptase.

Anticancer agents that present nonapoptotic cell death pathways are required for treating apoptosis-resistant pancreatic cancer. Here, we synthesized three fluorescent dithiocarbazate–copper complexes, {[CuII(L)­(Cl)] 1, [CuII 2(L)2(NO3)2] 2, and [CuII 2CuI(L)2(Br)3] 3}, to assess their antipancreatic cancer activities. Complexes 1–3 showed significantly greater cytotoxicity toward several pancreatic cancer cell lines with better IC50 than those of the HL ligand and cisplatin. Confocal fluorescence imaging showed that complex 3 was primarily localized in the mitochondria. Primarily, compound 3 also can be applied to in vivo imaging. Further studies revealed that complex 3 kills pancreatic cancer cells by triggering multiple mechanisms, including ferroptosis. Complex 3 is the first copper complex to evoke cellular events consistent with ferroptosis in cancer cells. Finally, it significantly retarded the ASPC-1 cells’ growth in a mouse xenograft model.

No abstract

The Zn(ii) complexes kill cells by p53-mediated mitochondrial pathway, inhibiting topoisomerase and inducing autophagy.

Multi-targeting of oncoproteins by a single molecule represents an effectual, rational, and an alternative approach to target therapy. We carried out a systematic study to reveal the mechanisms of action of newly synthesized Cu2+ compounds of 2-naphthalenol and 1-(((2-pyridinylmethyl)imino)methyl)- (C1 and C2). The antiproliferative activity of the as-synthesized complexes in three human cancer cell lines indicates their potential as multi-targeted antitumor agents. Relatively, C1 and C2 showed better efficacy in vitro relative to Cisplatin and presented promising levels of toxicity against A-549 cells. On the whole, the Cu2+ complexes exhibited chemotherapeutic effects by generating reactive oxygen species (ROS) and arresting the cell cycle in the G0/G1 phase by competent regulation of cyclin and cyclin-dependent kinases. Fascinatingly, the Cu2+ complexes were shown to activate the apoptotic and autophagic pathways in A-549 cells. These complexes effectively induced endoplasmic reticulum stress-mediated apoptosis, inhibited topoisomerase-1, and damaged cancer DNA through a ROS-mediated mechanism. The synthesized Cu2+ complexes established ROS-mediated targeting of multiple cell signaling pathways as a fabulous route for the inhibition of cancer cell growth.

No abstract

Only the [Cu(L)2] complex can significantly increase the intracellular ROS levels, leading to relatively high antiproliferative potency.