This work presents a multifaceted mechanism of the anticancer action of a 2-styrylquinazoline derivative. Extensive analysis of various aspects related to tyrosine kinase inhibition and effects on cellular targets at both the gene and protein levels revealed the potential of this IS20 compound for future research. This study presents a detailed analysis of the relationship between ABL and SRC kinase affecting the inhibition of the EGFR/mTOR signaling pathway in a non-obvious manner. The study was supported by experiments using various molecular biology techniques to confirm the induction of oxidative stress, inhibition of the cell cycle in the G2/M phase and the triggering of cell death via both the apoptosis and autophagy pathways. The cell models included those with different p53 protein status, which affected the cellular response in the form of altered Ndrg1 expression. Finally, the appropriate physicochemical properties of IS20 for adequate bioavailability and toxicity to the body were observed in an in vivo model.

• Klíčová slova
• Ndrg1, Anticancer drug, Apoptosis, Autophagy, Iron chelator, Oxidative stress, Styrylquinazoline, p53 protein,
• MeSH
• apoptóza účinky léků   MeSH
• autofagie účinky léků   MeSH
• chinazoliny * farmakologie   chemie   MeSH
• erbB receptory metabolismus   MeSH
• intracelulární signální peptidy a proteiny * genetika   metabolismus   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• oxidační stres * účinky léků   MeSH
• proteiny buněčného cyklu * genetika   metabolismus   MeSH
• protinádorové látky * farmakologie   chemie   MeSH
• signální transdukce účinky léků   MeSH
• TOR serin-threoninkinasy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chinazoliny * MeSH
• erbB receptory MeSH
• intracelulární signální peptidy a proteiny * MeSH
• N-myc downstream-regulated gene 1 protein MeSH Prohlížeč
• nádorový supresorový protein p53 MeSH
• proteiny buněčného cyklu * MeSH
• protinádorové látky * MeSH
• TOR serin-threoninkinasy MeSH

Multiple studies indicate that iron chelators enhance their anti-cancer properties by inducing NDRG1, a known tumor and metastasis suppressor. However, the exact role of NDRG1 remains controversial, as newer studies have shown that NDRG1 can also act as an oncogene. Our group recently introduced mitochondrially targeted iron chelators deferoxamine (mitoDFO) and deferasirox (mitoDFX) as effective anti-cancer agents. In this study, we evaluated the ability of these modified chelators to induce NDRG1 and the role of NDRG1 in breast cancer. We demonstrated that both compounds specifically increase NDRG1 without inducing other NDRG family members. We have documented that the effect of mitochondrially targeted chelators is at least partially mediated by GSK3α/β, leading to phosphorylation of NDRG1 at Thr346 and to a lesser extent on Ser330. Loss of NDRG1 increases cell death induced by mitoDFX. Notably, MDA-MB-231 cells lacking NDRG1 exhibit reduced extracellular acidification rate and grow slower than parental cells, while the opposite is true for ER+ MCF7 cells. Moreover, overexpression of full-length NDRG1 and the N-terminally truncated isoform (59112) significantly reduced sensitivity towards mitoDFX in ER+ cells. Furthermore, cells overexpressing full-length NDRG1 exhibited a significantly accelerated tumor formation, while its N-terminally truncated isoforms showed significantly impaired capacity to form tumors. Thus, overexpression of full-length NDRG1 promotes tumor growth in highly aggressive triple-negative breast cancer.

• Klíčová slova
• GSK3α/β, NDRG1, breast cancer, mitoDFO, mitoDFX, mitochondrial iron chelation, oncogene, tumor suppressor,
• Publikační typ
• časopisecké články MeSH

Combining low-dose chemotherapies is a strategy for designing less toxic and more potent childhood cancer treatments. We examined the effects of combining the novel thiosemicarbazones, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), or its analog, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), with the standard chemotherapies, celecoxib (CX), etoposide (ETO), or temozolomide (TMZ). These combinations were analyzed for synergism to inhibit proliferation of three pediatric tumor cell-types, namely osteosarcoma (Saos-2), medulloblastoma (Daoy) and neuroblastoma (SH-SY5Y). In terms of mechanistic dissection, this study discovered novel thiosemicarbazone targets not previously identified and which are important for considering possible drug combinations. In this case, DpC and Dp44mT caused: (1) up-regulation of a major protein target of CX, namely cyclooxygenase-2 (COX-2); (2) down-regulation of the DNA repair protein, O6-methylguanine DNA methyltransferase (MGMT), which is known to affect TMZ resistance; (3) down-regulation of mismatch repair (MMR) proteins, MSH2 and MSH6, in Daoy and SH-SY5Y cells; and (4) down-regulation in all three cell-types of the MMR repair protein, MLH1, and also topoisomerase 2α (Topo2α), the latter of which is an ETO target. While thiosemicarbazones up-regulate the metastasis suppressor, NDRG1, in adult cancers, it is demonstrated herein for the first time that they induce NDRG1 in all three pediatric tumor cell-types, validating its role as a potential target. In fact, siRNA studies indicated that NDRG1 was responsible for MGMT down-regulation that may prevent TMZ resistance. Examining the effects of combining thiosemicarbazones with CX, ETO, or TMZ, the most promising synergism was obtained using CX. Of interest, a positive relationship was observed between NDRG1 expression of the cell-type and the synergistic activity observed in the combination of thiosemicarbazones and CX. These studies identify novel thiosemicarbazone targets relevant to childhood cancer combination chemotherapy.

• Klíčová slova
• Dp44mT, DpC, celecoxib, combined anti-cancer treatment, etoposide, medulloblastoma, neuroblastoma, osteosarcoma, temozolomide, thiosemicarbazones,
• Publikační typ
• časopisecké články MeSH

Thiosemicarbazones (TSCs) are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di-substitution at the terminal N4 atom, which was previously identified to be critical for potent anti-cancer activity, was preserved through the incorporation of an N4-based piperazine or morpholine ring. The anti-proliferative activity of the novel TSCs were examined in a variety of cancer and normal cell-types. In particular, compounds 1d and 3c demonstrated the greatest promise as anti-cancer agents with potent and selective anti-proliferative activity. Structure-activity relationship studies revealed that the chelators that utilized "soft" donor atoms, such as nitrogen and sulfur, resulted in potent anti-cancer activity. Indeed, the N,N,S donor atom set was crucial for the formation of redox active iron complexes that were able to mediate the oxidation of ascorbate. This further highlights the important role of reactive oxygen species generation in mediating potent anti-cancer activity. Significantly, this study identified the potent and selective anti-cancer activity of 1d and 3c that warrants further examination.

• MeSH
• biologický transport účinky léků   MeSH
• kyselina askorbová metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• oxidace-redukce účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• racionální návrh léčiv * MeSH
• thiosemikarbazony chemická syntéza   chemie   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• železo chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kyselina askorbová MeSH
• protinádorové látky MeSH
• thiosemikarbazony MeSH
• železo MeSH