A novel manganese complex LMnAc selectively kills cancer cells by induction of ROS-triggered and mitochondrial-mediated cell death

Abstract

We previously identified a novel synthesized metal compound, LMnAc ([L 2 Mn 2 (Ac)(H 2 O) 2 ](Ac) (L=bis(2-pyridylmethyl) amino-2-propionic acid)). This compound exhibited significant inhibition on cancer cell proliferation and was more selective against cancer cells than was the popular chemotherapeutic reagent cisplatin. In this study, we further investigated the underlying molecular mechanisms of LMnAc-induced cancer cell death. We found that LMnAc achieved its selectivity against cancer cells through the transferrin-transferrin receptor system, which is highly expressed in tumor cells. LMnAc triggered cancer cells to commit autophagy and apoptosis, which was mediated by the mitochondrial pathway. Moreover, LMnAc disrupted mitochondrial function, resulting in mitochondrial membrane potential collapse and ATP reduction. In addition, LMnAc induced intracellular Ca 2+ overload and reactive oxygen species generation. Interestingly, its anticancer effect was significantly reduced following pretreatment with the antioxidant N-acetyl cysteine, indicating that reactive oxygen species triggered cell death. Altogether, our data suggest that LMnAc appears to be a selectively promising anticancer drug candidate. Mn(II) complex, selective, antitumor, autophagy, apoptosis, mitochondria, ROS Citation:Li X, Zhao KD, Guo WJ, Liu X, Liu J, Gao J, Chen QY, Bai YD. A novel manganese complex LMnAc selectively kills cancer cells by induction of ROS-triggered and mitochondrial-mediated cell death. Sci China Life Sci, 2014Sci, , 57: 998 -1010Sci, , doi: 10.1007 Following the landmark discovery of the biological activity of cisplatin [1], metal-based compounds have offered possibilities for the design of therapeutics to study and treat a variety of human diseases. To date, cisplatin remains one of the most effective anticancer drugs in clinical use, while more and more novel metal-based anticancer complexes have been and are being developed [25]. In recent years, much research has focused on Fe, Ru, Os, and, V. These studies have demonstrated that inducing ROS and cell death is a well-known mechanism of bioinorganic complexes [6]. Of all the metals, manganese (Mn), a required cofactor for many ubiquitous enzymes [7], is an essential trace element that plays a central role in the biochemistry and physiology of many living organisms. Simple Mn(II) salts have been reported to exert anti-proliferative effects on several cancer cell lines generally by induction of apoptotic cell death [8]. Moreover, the transport mechanism of Mn(II) in vivo may make Mn(II)-based compounds possible tumor-targets [5,9]. Recently, combining Mn(II) with other functional molecules has become a new strategy for the development of potent anti-tumor compounds. Ligands can significantly alter biological properties by limiting the adverse effects of metal ion overload and facilitate metal ion re-distribution [10]. For example, Mn(II) complexes containing thiosemicarbazone, hydrazone groups or chrysin were reported to have obvious anti-tumor effects [5,11,12].

A novel β-diiminato manganeseIII complex as the promising anticancer agent induces G0/G1 cell cycle arrest and triggers apoptosis via mitochondrial-dependent pathways in MCF-7 and MDA-MB-231 human breast cancer cells

“…Consequently, Mn-based complexes have been considered as a valuable source for the development of new anticancer agents. [19][20][21][22] On the other hand, ligands can modify the biological properties through the limitation of the side effects of metal ion overload and assist metal ion redistribution. [23][24][25] b-Diiminates are the wonderful class of chelating ligands.…”

Cefepime, a fourth-generation cephalosporin, in complex with manganese, inhibits proteasome activity and induces the apoptosis of human breast cancer cells

“…Since the discovery of the antitumor activity of cisplatin and its analogs, novel metal complexes have been studied extensively in chemotherapy (49). Mn is important in the biochemical and physiological processes of many living organisms (50). Mn is also highly expressed in some tumor tissues (51).…”

Manganese Schiff Base Complexes, Crystallographic Studies, Anticancer Activities, and Molecular Docking

“…However, anticancer activities entailing the MTT assay have more studies carried out using it than the SRB assay. Five groups of researchers specified using MTT assay to determine cell viability [22,24,37,78,83].…”

“…However, the rationale for the study of manganese coordination compounds as anticancer agents was first due to its physicochemical features clearly resembling those of iron which made manganese an important micronutrient for most creatures in the environment. Second, among all metals, manganese (Mn) is a needed cofactor for many prevalent enzymes (biological catalysts) [24][25][26][27][28]. ird, it is the second most abundant transition metal on the Earth's surface, indicating accessibility [29].…”