Novel imidazo[1,2‑a]pyridine inhibits AKT/mTOR pathway and induces cell cycle arrest and apoptosis in melanoma and cervical cancer cells

Aliwaini, Saeb; Awadallah, Adel Μ.; Morjan, Rami Y.; Ghunaim, Mariam Jamal; Alqaddi, Hala; Abuhamad, Asmaa Y.; Awadallah, Enas; Abughefra, Yasmin

doi:10.3892/ol.2019.10341

Cited by 11 publications

(16 citation statements)

References 33 publications

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“…The increases in the levels of p21 cell cycle regulator and cyclin D1 are commonly used as a markers for cell cycle arrest at the G1 stage (Aliwaini et al, 2019;Benzeno et al, 2004). Our results are similar to many previous studies which have indicated that the treatment of various cell lines (such as; Breast cancer, Human hepatocellular carcinoma, Liver cancer, Lung cancer, Melanoma, HeLa cervical cancer) by IPs-based compounds (e.g.…”

Section: Discussionsupporting

confidence: 90%

“…Our results are similar to many previous studies which have indicated that the treatment of various cell lines (such as; Breast cancer, Human hepatocellular carcinoma, Liver cancer, Lung cancer, Melanoma, HeLa cervical cancer) by IPs-based compounds (e.g. IP-Se-05; P-Se-06; contributed in a cell cycle arrest in the G1 and G2 cell cycle stage, as well as elevated concentrations of p21, p53 proteins and cyclin D1 (Lee et al, 2013;Jung et al, 2013;Hayakawa et al, 2018;Aliwaini et al, 2019). In the current study, IP-5 compound has been proven to carry out its cytotoxic effect by triggering extrinsic apoptosis as evident by the high level of PARP cleaved, Caspases 7 and Caspases 8.…”

Section: Discussionmentioning

confidence: 99%

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The Anticancer Effects of Novel Imidazo[1,2-a]Pyridine Compounds against HCC1937 Breast Cancer Cells

Altaher

Adris²,

Aliwaini

et al. 2022

Asian Pac J Cancer Prev

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Background: Anticancer drugs confront clinical obstacles such as drug resistance and adverse effects. Imidazo[1,2-a] pyridines (IPs) compounds have lately gained considerable interest as possible anticancer therapeutics due to their potent inhibitory function against cancers cells. This study was to determine the anticancer activities of three novel IPs (IP-5, IP-6, and IP-7) against the HCC1937 breast cancer cell line in vitro. Materials and Methods: The cytotoxic and anti-proliferative effects of IPs compounds in HCC1937 cells were determined by cell viability (MTT) assay, trypan blue assay, and clonogenic survival assay. Scratch motility assay was used to test the antimigration ability of the IPs. Western blot analysis was carried out to detect the level of apoptosis and cell cycle protein markers and to understand the mechanism of action of IPs compounds. Results: IP-5 and IP-6 have a strong cytotoxic impact against HCC1937 cells with IC50 values of 45µM and 47.7µM respectively. IP-7 possesses less cytotoxic effect against HCC1937 cells with IC50 of 79.6µM. Trypan blue assay showed that the three compounds induce significant cell death in the HCC1937 cells. Clonogenic and mammosphere assays demonstrated that IP-5 reduced the HCC1937 cells survival rate by more than 25.0% at 1000 cell concentrations. Western blotting analysis showed that IP-5 compound causes cell cycle arrest as noted by the increasing levels of p53 and p21 in treated cells. IP-5 induced an extrinsic apoptosis pathway as reveals from the increased activity of caspase 7, caspase 8, and the increasing level of PARP cleavage in treated cells. Also, IP-5 treated cells revealed segmented chromatin which is characteristic of apoptotic cells as shown by DAPI stain. Importantly, In comparison to control cells, IP-5-treated cells exhibited lower levels of pAKT. Conclusions: The novel three IPs compounds represent potential active anticancer compounds against HCC1937 breast cancer cells in vitro.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

The Anticancer Effects of Novel Imidazo[1,2-a]Pyridine Compounds against HCC1937 Breast Cancer Cells

Altaher

Adris²,

Aliwaini

et al. 2022

Asian Pac J Cancer Prev

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“…Furthermore, increasing γ -H2AX levels clearly indicated DNA fragmentation after treatment of glioblastoma cells with IP-Se-06. The observations by Aliwaini and collaborators [ 15 ] suggest that imidazopyridines may induce apoptosis through p53 regulation. In additions, our results corroborate those of Wang and collaborators [ 13 ], showing that novel imidazopyridine derivatives can exert anticancer activity by inducing mitochondrial pathway-mediated apoptosis and indicating such compounds as promising candidates for glioblastoma treatment [ 46 ] [ 16 ].…”

Section: Resultsmentioning

confidence: 99%

“…The ability of imidazo[1,2- a ]pyridine derivatives to inhibit Akt pathway and cell cycle progression in cancer cells has been recently reported. Aliwaini and collaborators [ 15 ] described that imidazo[1,2- a ]pyridine induces cell cycle arrest and apoptosis, while it is able to inhibit Akt/mTOR pathway in melanoma and cervical cancer cells. Yu and collaborators [ 14 ] demonstrated the biological effects of imidazo[1,2- a ]pyridine derivatives on the PI3K/mTOR dual inhibition, resulting in a significant inhibition of tumor growth in colorectal carcinoma xenografts.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, IPs have attracted critical attention due to the interesting properties exhibited in different types of molecular mechanisms in cancer chemotherapy [ 12 ] [ 13 ]. These compounds proved to be potent PI3K/mTOR dual inhibitors with excellent kinase selectivity [ 14 ], inducing cell cycle arrest and apoptosis [ 15 ]. In this regard, Quattrini and collaborators [ 16 ] reported the evidence of IPs derivatives as novel drug candidates for the treatment of glioblastoma.…”

Section: Introductionmentioning

confidence: 99%

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IP-Se-06, a Selenylated Imidazo[1,2-a]pyridine, Modulates Intracellular Redox State and Causes Akt/mTOR/HIF-1α and MAPK Signaling Inhibition, Promoting Antiproliferative Effect and Apoptosis in Glioblastoma Cells

Santos

Rafique

Saba

et al. 2022

Oxidative Medicine and Cellular Longevity

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Glioblastoma multiforme (GBM) is a notably lethal brain tumor associated with high proliferation rate and therapeutic resistance, while currently effective treatment options are still lacking. Imidazo[1,2-a]pyridine derivatives and organoselenium compounds are largely used in medicinal chemistry and drug development. This study is aimed at further investigating the antitumor mechanism of IP-Se-06 (3-((2-methoxyphenyl)selanyl)-7-methyl-2-phenylimidazol[1,2-a]pyridine), a selenylated imidazo[1,2-a]pyridine derivative in glioblastoma cells. IP-Se-06 exhibited high cytotoxicity against A172 cells ( I C 50 = 1.8 μ M ) and selectivity for this glioblastoma cell. The IP-Se-06 compound has pharmacological properties verified in its ADMET profile, especially related to blood-brain barrier (BBB) permeability. At low concentration (1 μM), IP-Se-06 induced intracellular redox state modulation with depletion of TrxR and GSH levels as well as inhibition of NRF2 protein. IP-Se-06 also decreased mitochondrial membrane potential, induced cytochrome c release, and chromatin condensation. Furthermore, IP-Se-06 induced apoptosis by decreasing levels of Bcl-xL while increasing levels of γ-H2AX and p53 proteins. Treatment with IP-Se-06 induced cell cycle arrest and showed antiproliferative effect by inhibition of Akt/mTOR/HIF-1α and ERK 1/2 signaling pathways. In addition, IP-Se-06 displayed significant inhibition of p38 MAPK and p-p38, leading to inhibition of inflammasome complex proteins (NLRP3 and caspase-1) in glioblastoma cells. These collective findings demonstrated that IP-Se-06 is a bioactive molecule that can be considered a candidate for the development of a novel drug for glioblastoma treatment.

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Imidazopyridine chalcones as potent anticancer agents: Synthesis, single‐crystal X‐ray, docking, DFT and SAR studies

Soumyashree,

Reddy,

Nagarajaiah

et al. 2023

Archiv der Pharmazie

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New imidazopyridine–chalcone analogs were synthesized through the Claisen–Schmidt condensation reaction. The newly synthesized imidazopyridine‐chalcones (S1–S12) were characterized using spectroscopic and elemental analysis. The structures of compounds S2 and S5 were confirmed by X‐ray crystallography. The global chemical reactivity descriptor parameter was calculated using theoretically (DFT‐B3LYP‐3‐211, G) estimated highest occupied molecular orbital and lowest unoccupied molecular orbital values and the results are discussed. Compounds S1–S12 were screened on A‐549 (lung carcinoma epithelial cells) and MDA‐MB‐231 (M.D. Anderson‐Metastatic Breast 231) cancer cell lines. Compounds S6 and S12 displayed exceptional antiproliferative activity against lung A‐549 cancer cells with IC50 values of 4.22 and 6.89 µM, respectively, compared to the standard drug doxorubicin (IC50 = 3.79 μM). In the case of the MDA‐MB‐231 cell line, S1 and S6 exhibited exceptionally superior antiproliferative activity with IC50 of 5.22 and 6.50 μM, respectively, compared to doxorubicin (IC50 = 5.48 μM). S1 was found to be more active than doxorubicin. Compounds S1–S12 were tested for their cytotoxicity on human embryonic kidney 293 cells, which confirmed the nontoxic nature of the active compounds. Further molecular docking studies verified that compounds S1–S12 have a higher docking score and interacted well with the target protein. The most active compound S1 interacted well with the target protein carbonic anhydrase II in complex with pyrimidine‐based inhibitor, and S6 with human Topo IIα ATPase/AMP‐PNP. The results suggest that imidazopyridine‐chalcone analogs may serve as new leads as anticancer agents.

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Novel imidazo[1,2‑a]pyridine inhibits AKT/mTOR pathway and induces cell cycle arrest and apoptosis in melanoma and cervical cancer cells

Cited by 11 publications

References 33 publications

The Anticancer Effects of Novel Imidazo[1,2-a]Pyridine Compounds against HCC1937 Breast Cancer Cells

The Anticancer Effects of Novel Imidazo[1,2-a]Pyridine Compounds against HCC1937 Breast Cancer Cells

IP-Se-06, a Selenylated Imidazo[1,2-a]pyridine, Modulates Intracellular Redox State and Causes Akt/mTOR/HIF-1α and MAPK Signaling Inhibition, Promoting Antiproliferative Effect and Apoptosis in Glioblastoma Cells

Imidazopyridine chalcones as potent anticancer agents: Synthesis, single‐crystal X‐ray, docking, DFT and SAR studies

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