The thiosemicarbazone, DpC, broadly synergizes with multiple anti-cancer therapeutics and demonstrates temperature- and energy-dependent uptake by tumor cells

Mahendiran, Dharmasivam; Azad, Mahan Gholam; Afroz, Rizwana; Richardson, Vera; Jansson, Patric J.; Richardson, Des R.

doi:10.1016/j.bbagen.2022.130152

Cited by 13 publications

(16 citation statements)

References 75 publications

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“…Considering this, we reported that combining DpC or Dp44mT with tamoxifen and various other chemotherapeutics demonstrates synergistic anti-proliferative activity against BC cells [95][96][97]. This beneficial activity could assist in overcoming tamoxifen resistance, which is a major clinical hurdle in treating deadly ER-positive BC [11].…”

Section: Discussionmentioning

confidence: 98%

“…Additionally, considering the ability of DpC to inhibit multiple key pathways [95][96][97][98] that promote endocrine resistance also suggests it could be a superior strategy for BC treatment that potentially overcomes tamoxifen resistance [95]. Traditional drug design in terms of cancer therapy dictates 1 drug with 1 target that unfortunately leads to deadly resistance, such as with tamoxifen [32].…”

Section: Discussionmentioning

confidence: 99%

“…Hence, the ability of Dp44mT and DpC to inhibit these additional arms of ER-α signaling may have important implications for overcoming tamoxifen resistance. Considering this, we reported that combining DpC or Dp44mT with tamoxifen and various other chemotherapeutics demonstrates synergistic anti-proliferative activity against BC cells [95–97]. This beneficial activity could assist in overcoming tamoxifen resistance, which is a major clinical hurdle in treating deadly ER-positive BC [11].…”

Section: Discussionmentioning

confidence: 99%

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An Innovative Non-Hormonal Strategy Targeting Redox Active Metals to Down-Regulate Estrogen-, Progesterone-, Androgen- and Prolactin-Receptors in Breast Cancer

Shehadeh-Tout

Milioli

Roslan

et al. 2023

Preprint

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Estrogen receptor-α (ER-α) is a key driver of breast cancer (BC) targeted by tamoxifen. However, tamoxifen resistance is a major problem. An important mechanism of resistance is the activation of EGFR/HER2/HER3 signaling and other hormone receptors (androgen receptor (AR), progesterone receptor (PR), prolactin receptor (PRL-R)) that intrinsically activate ER-α. Hence, therapeutics targeting multiple receptors, rather than ER-α alone, would be extremely useful and may overcome tamoxifen resistance. This study examined the activity of redox-active di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), on the expression and activation of crucial hormone receptors, their co-factors, and key resistance pathways in ER-α-positive BC. Strikingly, DpC differentially regulated 106 estrogen-response genes with Sankey diagram analysis demonstrating this was linked to decreased mRNA levels of 4 central hormone receptors involved in BC pathogenesis, namely ER, PR, AR, and PRL-R. Mechanistic dissection demonstrated that due to DpC and Dp44mT binding metal ions, these agents caused a pronounced decrease in ER-α, AR, PR, and PRL-R protein expression. Ablation of the metal-binding site in the thiosemicarbazone totally prevented its suppressive activity, demonstrating a unique non-hormonal mechanism. DpC and Dp44mT also inhibited EGFR, HER2, and HER3 activation, their downstream signaling, and the expression of co-factors that promote ER-α transcriptional activity, including SRC3, NF-κB p65, and SP1. In vivo, DpC was highly tolerable and effectively inhibited ER-α-positive BC growth. In conclusion, through a bespoke non-hormonal mechanism targeting redox active metals, Dp44mT and DpC disrupt multiple key inter-receptor interactions between PR, AR, PRL-R, and tyrosine kinases that act with ER-α to promote BC, constituting an innovative therapeutic approach.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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An Innovative Non-Hormonal Strategy Targeting Redox Active Metals to Down-Regulate Estrogen-, Progesterone-, Androgen- and Prolactin-Receptors in Breast Cancer

Shehadeh-Tout

Milioli

Roslan

et al. 2023

Preprint

Self Cite

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“…In second-generation thiosemicarbazone compounds wherein the terminal H of N4 was substituted with an alkyl group, compound 6 showed potential application prospects in antitumor ( Lovejoy et al, 2012 ). Compound 6 exhibits higher anti-tumour activity in vivo and demonstrates considerable improvement in tolerability when administered orally or intravenously compared with first-generation thiosemicarbazone compounds ( Stariat et al, 2013 ; Maqbool et al, 2020 ; Dharmasivam et al, 2022 ). Thiosemicarbazones combine with intracellular copper (Cu) ions to produce stable Cu complexes once they are inside the lysosome.…”

Section: Thiosemicarbazone Ligands In a Clinical Trialmentioning

confidence: 99%

“…This diversity is not only reflected in the metal and its oxidation state but also in the diversity of ligands that form coordination bonds with it and the different coordination modes ( Matesanz et al, 2021a ). Many literatures report that thiosemicarbazone ligands and their metal complexes have significant antitumor activity against lung cancer, liver cancer, colon cancer, breast cancer, neuroma and other tumors ( Onodera et al, 2007 ; Lovejoy et al, 2012 ; Maqbool et al, 2020 ; Dharmasivam et al, 2022 ). Among many cancers, lung cancer has been the most common disease affecting human health.…”

Section: Introductionmentioning

confidence: 99%

Advances in thiosemicarbazone metal complexes as anti-lung cancer agents

Bai

Zheng²,

Qi³

2022

Front. Pharmacol.

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The great success of cisplatin as a chemotherapeutic agent considerably increased research efforts in inorganic biochemistry to identify more metallic drugs having the potential of treating lung cancer. Metal coordination centres, which exhibit a wide range of coordination numbers and geometries, various oxidised and reduced states and the inherent ligand properties offer pharmaceutical chemists a plethora of drug structures. Owing to the presence of C=N and C=S bonds in a thiosemicarbazone Schiff base, N and S atoms in its hybrid orbital has lone pair of electrons, which can generate metal complexes with different stabilities with most metal elements under certain conditions. Such ligands and complexes play key roles in the treatment of anti-lung cancer. Research regarding metallic anti-lung cancer has advanced considerably, but there remain several challenges. In this review, we discuss the potential of thiosemicarbazone Schiff base complexes as anti-lung cancer drugs, their anti-cancer activities and the most likely action mechanisms involving the recent families of copper, nickel, platinum, ruthenium and other complexes.

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Cytotoxic pathways activated by multifunctional thiosemicarbazones targeting sigma-2 receptors in breast and lung carcinoma cells

Kopecka,

Barbanente,

Vitone

et al. 2023

Pharmacol. Rep

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Background Multifunctional thiosemicarbazones (TSCs) able to bind sigma receptors and chelate metals are considered as a promising avenue for the treatment of pancreatic cancer due to the encouraging results obtained on in vitro and in vivo models. Here, we assessed the biochemical mechanism of these TSCs also on lung (A549) and breast (MCF7) cancer cells. Methods The density of sigma-2 receptors in normal (BEAS-2B and MCF10A) and in lung and breast (A549 and MCF7) cancer cells was evaluated by flow cytometry. In these cells, cytotoxicity (MTT assay) and activation of ER- and mitochondria-dependent cell death pathways (by spectrofluorimetric assays to measure Caspases 3/7/9; qRT-PCR detection of GRP78, ATF6, IRE1, PERK; MitoSOX, DCFDA-AM and JC-1 staining), induced by the TSCs FA4, MLP44, PS3 and ACThio1, were evaluated. Results FA4 and PS3 exerted more potent cytotoxicity than MLP44 and ACThio1 in all cancer cell lines, where the density of sigma-2 receptors was higher than in normal cells. Remarkably, FA4 promoted ER- and mitochondria-dependent cell death pathways in both cell models, whereas the other TSCs had variable, cell-dependent effects on the activation of the two proapoptotic pathways. Conclusions Our data suggest that FA4 is a promising compound that deserves to be further studied for lung and breast cancer treatment. However, the other multifunctional TSCs also hold promise for the development of therapies towards a personalized medicine approach. Indeed, the presence of the sigma-2 receptor-targeting moiety would lead to a more specific tumor delivery embracing the characteristics of individual tumor types.

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The thiosemicarbazone, DpC, broadly synergizes with multiple anti-cancer therapeutics and demonstrates temperature- and energy-dependent uptake by tumor cells

Cited by 13 publications

References 75 publications

An Innovative Non-Hormonal Strategy Targeting Redox Active Metals to Down-Regulate Estrogen-, Progesterone-, Androgen- and Prolactin-Receptors in Breast Cancer

An Innovative Non-Hormonal Strategy Targeting Redox Active Metals to Down-Regulate Estrogen-, Progesterone-, Androgen- and Prolactin-Receptors in Breast Cancer

Advances in thiosemicarbazone metal complexes as anti-lung cancer agents

Cytotoxic pathways activated by multifunctional thiosemicarbazones targeting sigma-2 receptors in breast and lung carcinoma cells

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