The rhenium(I)-diselenoether anticancer drug targets ROS, TGF-β1, VEGF-A, and IGF-1 in an in vitro experimental model of triple-negative breast cancers

Abstract

The rhenium(I)-diselenoether complex (Re-diSe) is a rhenium tricarbonyl-based drug chelated by a diselenoether ligand. In this work, we compared its inhibitory effects on the hormone-independent MDA-MB231cancer line and other different cancer cell lines after an exposure time of 72 h by MTT assays. The sensitivity of MDA-MB231 was in the same range than the hormone dependent MCF-7 breast cancer, the PC-3 prostate and HT-29 colon cancer cells, while the A549 lung and the HeLa uterine cancer cells were less sensitive. We compared the inhibitory effects of Re-diSe and of its diselenide ligand (di-Se) on MDAMB231 and a normal HEK-293 human embryonic cell line, after 72 h and 120 h of exposure. The cytotoxicity was also studied by flow cytometry using ethidium bromide assays, as well as the effects on the ROS production by DFCA-test, while the levels of TGF-β1, VEGF-A, IGF-1 were addressed by ELISA tests. The dose required to inhibit 50% of the proliferation (IC50) ofMDAMB231 breast cancer cells decreased with the time of exposure to 120 h, while the free ligand (di-Se) was found poorly active, demonstrating the important role of Re in this Re-diSe combination. The cytotoxic effects of Re-diSe were highly selective for cancer cells, with a significant increase of the number of dead cancer cells at 5 μM for an exposure time of 120 h, while normal cells were not affected. A remarkable and significant decrease of the production of ROS together with a decrease of VEGF-A, TGF-β1, and IGF-1 by the cancer cells were also observed when cancer cells were exposed to Re-diSe.

Rhenium‐Based Complexes and in Vivo Testing: A Brief History

“…This involved a Re atom coordinated equatorially to two selenium atoms with the complex being stable, water soluble and lipophilic. The cytotoxic and antitumour effects of selenium have been well documented previously [21–25] . Complex V had previously shown impressive cytotoxicity against the MCF‐7 breast cancer cell line with an IC 50 value of 4.75 μM [25] .…”

Recent Emergence of Rhenium(I) Tricarbonyl Complexes as Photosensitisers for Cancer Therapy

“…Complex 14 showed good cytotoxic effect towards breast cancer cells and mice bearing with MDA-MB-231 Luc+ human breast cancer cells. Complex 14 was previously reported with an anticancer effect (IC 50 : 10 µM) towards MDA-MB-23l cells [ 115 ] and (IC 50 : 4.75 µM) MCF-7 breast cancer cells [ 116 ] before it proceeded to in vivo testing. Complex 14 , orally administered was then tested on mice that were transplanted with breast cancer cells as mentioned and it was found that a 10 mg/kg dose was safe, non-toxic, tolerable, and able to lessen tumour growth for at least four weeks of treatment [ 117 , 118 ].…”

Highly Potent Rhenium(I) Tricarbonyl Complexes with Dual Anticancer and Anti-Angiogenic Activity Against Colorectal Carcinoma

“…including N−O, 12,13 O-O, 14 P-P 15 and Se-Se chelates, [16][17][18][19][20] N,N,N-tridentate chelates [21][22][23][24][25][26] or bridged di-or tri-nuclear alkoxo/hydroxo are also known. [27][28][29] Additionally, but rarer, phototoxic Re complexes capable of either generating reactive oxygen species (ROS) or liberating CO have also been identified.…”

“…The anticancer activity of fac-[Re(CO)3] + compounds has been tested on several different cancer cell lines. The majority of the studies were focused on antiproliferative effects on cervical, 30-33, 47, 51, 57-61 ovarian, 62,63 breast, 12,20,25,[64][65][66] and epithelial adenocarcinoma 24,49,67,68 cell lines showing IC50 values as low as e.g. 0.1 (HeLa), 30 1 (MCF-7), 15 0.75 (A549), 67 4 (NB69 and H4 cells) μM.…”

“…0.1 (HeLa), 30 1 (MCF-7), 15 0.75 (A549), 67 4 (NB69 and H4 cells) μM. 12 To our knowledge, only a few rhenium(I) carbonyl complexes have been tested against colon cancer cell lines 16,20,[69][70][71][72][73][74][75] (some of which are shown in (Table 3). As evident from…”