Insights into the in vitro Anticancer Effects of Diruthenium‐1

Abstract

The in vitro anticancer activity of the dinuclear trithiolato-bridged arene ruthenium complex diruthenium-1 (DiRu-1) was evaluated against a panel of human cancer cell lines used as in vitro models for hepatocellular carcinoma (HepG2 cells), estrogen-responsive breast adenocarcinoma (MCF-7 cells), and triple-negative breast adenocarcinoma (MDA-MB-231 cells). DiRu-1 is highly cytotoxic to these cell lines, demonstrating half-maximal inhibitory concentrations (IC ) in the low-nanomolar range (77±1.4 to 268.2±4.4 nm). The main molecular mechanisms responsible for the high cytotoxicity of DiRu-1 against the most responsive MCF-7 cell line (IC =77±1.4 nm) were investigated on the basis of the capacity of DiRu-1 to induce oxidative stress, apoptosis, and DNA damage, and to inhibit the cell cycle and proliferation. The results show that DiRu-1 triggers caspase-dependent apoptosis in MCF-7 cells on both the intrinsic and extrinsic pathways. Moreover, the Ru complex also causes necrosis, mitotic catastrophe, and autophagy. DiRu-1 increases the intracellular levels of reactive oxygen species (ROS), which play a significant role in its cytotoxicity and pro-apoptotic activity. An important mechanism of the anticancer activity of DiRu-1 appears to be the induction of DNA lesions, mainly due to apoptotic DNA fragmentation and cell-cycle arrest at the G /M checkpoint. These changes are correlated with the concentration of DiRu-1, the duration of the cell treatment, and the post-treatment time.

Antiproliferative effects of ruthenium-based nucleolipidic nanoaggregates in human models of breast cancer in vitro: insights into their mode of action

“…Nevertheless, the existence of other non-apoptotic nor necrotic cell death pathways, triggered upon exposure to ruthenium-containing nanoaggregates we have documented in breast cancer models, needs further and more targeted studies. According to our previous findings24 and to recent literature reports3652, it cannot be excluded that the simultaneous activation of different mechanisms of cell death can be caused by multiple potential interactions at the subcellular/molecular level, both nuclear and cytosolic. Nevertheless, the activation of multiple death pathways by metal-based chemotherapeutics in aggressive cancer diseases with limited treatment options is a largely desired goal, in order to possibly restrict the onset of chemoresistance as well as to efficiently counteract uncontrolled proliferation.…”

“…Therefore, classical chemotherapy is currently the only drug-based option in the therapeutic armamentarium, and metal-based chemotherapy is also emerging as an upcoming treatment modality especially in TNBC35. Although new types of ruthenium complexes with superior anticancer activity in vitro have been meanwhile reported36, the induction of comparable or even greater cytotoxic effects than cisplatin have been herein confirmed for nucleolipidic Ru(III) formulations. Then, aiming at an in-depth investigation of their mode of action, we have shown that amphiphilic ruthenium complexes, properly delivered by suitable nano-systems, are able to kill cancer cells by activating specific apoptotic processes, coupled in some cases to cellular autophagy.…”

Encapsulation of the Dinuclear Trithiolato‐Bridged Arene Ruthenium Complex Diruthenium‐1 in an Apoferritin Nanocage: Structure and Cytotoxicity

“…It has been reported that DiRu‐1 triggers the production of ROS in MCF‐7 cells . Therefore, oxidative stress was evaluated by measuring intracellular ROS in cells incubated with DiRu‐1 or DiRu‐1‐encapsulated AFt for various periods of time (Figure A,B).…”

“…The most active member of this family is [(η 6 ‐ p ‐Me‐C 6 H 4 i Pr) 2 Ru 2 (μ 2 ‐S‐ p ‐C 6 H 4 t Bu) 3 ]Cl, termed diruthenium‐1 or DiRu‐1 (Figure ) . This compound is very toxic in vitro toward hepatocellular carcinoma (HepG2 cells), estrogen‐responsive breast adenocarcinoma (MCF‐7 cells) and BT549 cells, triple‐negative breast adenocarcinoma (MDA‐MB‐231 cells), human ovarian cancer (A2780 cells), and the cisplatin‐resistant cell line A2780cis, with IC 50 values in the low nanomolar range . Recent in vivo studies, have demonstrated that these complexes have potential as anticancer drugs, especially DiRu‐1, which significantly prolongs the survival of tumor‐bearing mice .…”

Recent developments in the nanostructured materials functionalized with ruthenium complexes for targeted drug delivery to tumors

“…The cytotoxic and proapoptotic effects of DiRu-1 were attributed to the increase in intracellular levels of ROS, while the anticancer effect was due to the induction of DNA lesions caused by apoptotic DNA fragmentation and cell-cycle arrest at the G 2 /M checkpoint. 23 In summary, the diverse modes of action of Ru anticancer drugs likely enhanced their anticancer activities and minimized the potential for cancer cells to …”