Combination of Ruthenium Complex and Doxorubicin Synergistically Inhibits Cancer Cell Growth by Down-Regulating PI3K/AKT Signaling Pathway

Abstract

Combinational use of drugs has been a common strategy in cancer treatment because of synergistic advantages in reducing dose and toxicity, minimizing or delaying drug resistance. To improve the efficacy of chemotherapy, various potential combinations have been investigated. Ruthenium complex is considered a potential alternative of the platinum-based drugs due to its significant efficacy and safety. Previously, we reported that ruthenium(II) complex ( -Ru1) has great anticancer potential and minor toxicity toward normal tissues. However, the therapeutic efficacy and mechanism of action of ruthenium(II) complex combined with other anticancer drugs is still unknown. Here, we investigated the combinational effect of -Ru1 and doxorubicin in different cancer cells. The data assessed by Chou-Talalay method showed significant synergism in MCF-7 cells. Furthermore, the results in antiproliferation efficacy indicated that the combination showed strong cytotoxicity and increasing apoptosis of MCF-7 cells in 2D and 3D multicellular tumor spheroids (MCTSs). Significant inhibition of MCF-7 cells accompanied with increased ROS generation was observed. Furthermore, the expression of PI3K/AKT was significantly down-regulated, while the expression of PTEN was strongly up-regulated in cells treated with combination of -Ru1 and doxorubicin. The expression of NF-κB and XIAP decreased while the expression of P53 increased and associated with apoptosis. These findings suggest that the combination of ruthenium complex and doxorubicin has a significant synergistic effect by down-regulating the PI3K/AKT signaling pathway in MCF-7 cells. This study may trigger more research in ruthenium complex and combination therapy that will be able to provide opportunities for developing better therapeutics for cancer treatment.

Investigation of the Effects and Mechanisms of Anticancer Action of a Ru(II)‐Arene Iminophosphorane Compound in Triple Negative Breast Cancer Cells

“…[61] This pathway is frequently altered in TNBC, with mutations and alterations seen in roughly 25 % of TNBCs. [62] Down regulation of this pathway has resulted in the inhibition of cancerous growth for other ruthenium complexes [46,63] although it has not been tested extensively in TNBC. To validate results, M-CSF protein expression levels following Ru-IM (1) treatment were evaluated using western blot analysis (Supporting Information Figure 3).…”

Combining PARP Inhibition with Platinum, Ruthenium or Gold Complexes for Cancer Therapy

“…However, studies into the combination of ruthenium complexes with other compounds are uncommon due to several uncertain factors, including on how to select compounds for combination and the potential mechanism(s) of drug synergism [125] . Nevertheless, several studies with first‐line anti‐cancer agents, including the combinations of Ru(II) complex/radiation, [126] NAMI‐A/doxorubicin, [127] RAPTA‐C/doxorubicin, [67] Ru(II) complex/doxorubicin, [128] NKP1339/sorafenib, [129] and RAPTA‐C/erlotinib [130] have been explored both in vitro and in vivo . Moreover, the combination of NAMI‐A/gemcitabine has been clinically investigated in phase I/II trials for NSCLC patients [131] .…”

A photoarchitectonic hydrogel for synergistic in vitro chemo–phototherapy of breast cancer

“…Therefore, increased green fluorescence suggests a higher level of ROS production. 71 When treated with chemo–phototherapeutic hydrogel (DOX@CDs–ZnPc-PP H) only under dark conditions, the cells represent a state with low ROS levels (Fig. 6(e)).…”