Biological evaluation of 2-arylidene-4, 7-dimethyl indan-1-one (FXY-1): a novel Akt inhibitor with potent activity in lung cancer

Rajagopalan, Prasanna; Alahmari, Khalid A.; Elbessoumy, Ashraf A; Balasubramaniam, Meenakshisundaram; Radhakrishnan, S.; Shariff, Mohammed Eajaz Ahmed; Chandramoorthy, Harish C.

doi:10.1007/s00280-015-2956-8

Cited by 26 publications

(27 citation statements)

References 39 publications

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“…Our results were in agreement and another way of confirming the induction of apoptosis by MLT-401. It is well established from the literature [37] and our own previous investigations [17, 21] have shown that the cells which get accumulated in the M4 fraction were apoptotic cells.…”

Section: Discussionmentioning

confidence: 92%

“…Many studies have assessed various other arylidene derivatives exhibiting antibacterial [23], antifungal [24], or anticancer [25, 26] activities. Other members of our study group have also reported anti-cancer properties [17, 21] for a few derivatives of this family.…”

Section: Discussionmentioning

confidence: 99%

“…The selective inhibition of cancerous cells over normal cells both in normoxic and marginal hypoxic conditions shows that the molecule works downstream of the hypoxic conditions. Some arylidene derivatives have been shown previously to work on upstream pathways, such as the involvement of the Akt pathways ras and p53 [17, 28, 29]. It may be further noted that the involvement of various upstream and downstream nodal pathways is characteristic of the source of cancer models [30, 31].…”

Section: Discussionmentioning

confidence: 99%

“…To address these physiological concerns, the current study was designed to use the arylidene derivative MLT-401, an indanone compound known for its biologic activity, with special reference to its anti-tumor/cancer efficacy on various cancer models [15, 16]. The selection of MLT-401 was based on its previously reported structural similarity with arylidene indanone molecules having profound anti-tumor activity [17]. Further, these indanone compounds have not been affected by the drug resistance as observed with many other cancer drugs.…”

Section: Introductionmentioning

confidence: 99%

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Natural Hypoxia is Not a Limiting Factor in Evaluating the Novel Arylidene Derivative MLT-401 Against an In Vitro Colorectal Cancer Model

Bin-Jaliah¹

2018

Cell Physiol Biochem

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Background/Aims: Cancer cells in vivo develop resistance to many anti-tumor drugs. One known factor to influence such drug resistance is hypoxia, which is an important component of the tumor microenvironment. Standard cancer lines mostly do not exhibit a cellular hypoxic microenvironment and there is a paucity of information on the efficacy of lead molecules in both cellular- and environment-induced hypoxic conditions. Therefore, in the present study, we have evaluated the efficacy of the arylidene derivative MLT-401, a lead molecule showing activity against colorectal cancer model using the HCT 116 cell line and CCD-80-C control cells in normoxic and natural (marginal) hypoxic conditions, which is usually observed in high-altitude regions. Methods: The efficacy of MLT-401 on HCT 116 and CCD-80-C cells were tested in both normoxia and marginal hypoxia conditions. MTT assay was used to evaluate cell proliferation, Annexin V binding assay for apoptotic cell quantification and PI staining for cell cycle were done by flow cytometry. Induction of pro-apoptotic marker BAX and anti-apoptotic Bcl-2 were assessed by western blot. Bcl-2/BAX ratio was calculated based on protein expression by western blotting and bands were quantified by Image J software. Results: Analysis of cell proliferation showed an average 10-fold reduction in the inhibition of HCT 116 cells in hypoxic conditions with approximately 500 nM MLT-401, while there was no significant change noted in marginal hypoxic conditions. A proportionate increase in the number of apoptotic cells and large M4 fraction of 10.5% and 26.7% of HCT116 against 6.3% of control cells in cell cycle assessment with MLT-401 concentrations ranging from 250 to 500 nM respectively clearly demonstrated anti-cancer activity. A Bcl-2/BAX ratio of < 1 showed that the induction of apoptosis was the gross mechanism underlying the inhibition of HCT 116 cells by MLT-401. Conclusion: Collectively, these results show MLT-401 as an effective anti-colorectal cancer lead molecule irrespective of normoxia or natural hypoxia.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Natural Hypoxia is Not a Limiting Factor in Evaluating the Novel Arylidene Derivative MLT-401 Against an In Vitro Colorectal Cancer Model

Bin-Jaliah¹

2018

Cell Physiol Biochem

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“…The p53 signaling pathway serves an important role in apoptosis in lung cancer (34,35). Mutations to p53 protein are common in lung carcinoma (36); p53 has a antitumorigenic effect in NSCLC (37).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of GluA2 induces apoptosis in non-small-cell lung cancer A549 cells through the p53 signaling pathway

Zhang

Yang

2017

Oncology Letters

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Abstract. α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are important glutamatergic receptors that mediate fast excitatory synaptic transmission in the brain. Previous studies have demonstrated that glutamate ionotropic receptor AMPA type subunit 2 (GluA2), one of the four subunits that comprise AMPA receptors, is a potential novel marker for poor prognosis in patients with human lung cancer. However, the mechanisms of GluA2-induced apoptosis, proliferation and migration in lung cancer remain unknown. The present study aimed to explore the mechanisms underlying these effects of GluA2 in human lung cancer by silencing GluA2 in A549 cells. Using the Cell Counting Kit-8 assay, western blot analysis and acridine orange/ethidium bromide staining, downregulation of GluA2 was revealed to significantly inhibit the proliferation and significantly promote the apoptosis of A549 cells. Knockdown of GluA2 was also revealed to be associated with increased caspase-3 activity, increased Bcl-2-associated X protein and Bcl-2-associated death promoter (Bad) expression, and decreased expression of B-cell lymphoma-2, p-Bad and X-linked inhibitor of apoptosis protein. In addition, GluA2 silencing upregulated cellular tumor antigen p53 (p53)/p21Cip1/Waf1 /p16 INK4a protein.In conclusion, these results indicate that the effects of GluA2 in lung cancer are mediated by the caspase-3 and p53/p21Cip1/Waf1 /p16 INK4a signaling pathways. Therefore, GluA2 may be a potential novel therapeutic target for the treatment of lung cancer.

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FCX‐146, a potent allosteric inhibitor of Akt kinase in cancer cells: Lead optimization of the second‐generation arylidene indanone scaffold

Balasubramaniam

Lakkaniga

Dera

et al. 2020

Biotech and App Biochem

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Akt, a serine‐threonine protein kinase, is regulated by class‐I PI3K signaling. Akt regulates a wide variety of cell processes including cell proliferation, survival, and angiogenesis through serine/threonine phosphorylation of downstream targets including mTOR and glycogen‐synthase‐kinase‐3‐beta (GSK3β). Targeting cancer‐specific overexpression of Akt protein could be an efficient way to control cancer‐cell proliferation. However, the ATP‐competitive inhibitors are challenged by the highly conserved ATP binding site, and by competition with high cellular concentrations of ATP. We previously developed an allosteric inhibitor, 2‐arylidene‐4, 7‐dimethyl indan‐1‐one (FXY‐1) that showed promising activity against several lung cancer models. In this work, we designed a congeneric series of molecules based on FXY‐1 and optimized lead based on computational, in vitro assays. Computational screening followed by enzyme‐inhibition and cell‐proliferation assays identified a derivative (FCX‐146) as a new lead molecule with threefold greater potency than the parent compound. FCX‐146 increased apoptosis in HL‐60 cells, mediated in part through decreased expression of antiapoptotic Bcl‐2 protein and increased levels of Bax‐2 and Caspase‐3. Molecular‐dynamic simulations showed stable binding of FCX‐146 to an allosteric (i.e., noncatalytic) pocket in Akt. Together, we propose FCX‐146 as a potent second‐generation arylidene indanone compound that binds to the allosteric pocket of Akt and potently inhibits its activation.

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Biological evaluation of 2-arylidene-4, 7-dimethyl indan-1-one (FXY-1): a novel Akt inhibitor with potent activity in lung cancer

Abstract: Collectively, our results suggest DNA damage-mediated activation by FXY-1 in lung cancer cells leading to extensive apoptosis through the mitochondrial pathway.

Cited by 26 publications

References 39 publications

Natural Hypoxia is Not a Limiting Factor in Evaluating the Novel Arylidene Derivative MLT-401 Against an In Vitro Colorectal Cancer Model

Natural Hypoxia is Not a Limiting Factor in Evaluating the Novel Arylidene Derivative MLT-401 Against an In Vitro Colorectal Cancer Model

Knockdown of GluA2 induces apoptosis in non-small-cell lung cancer A549 cells through the p53 signaling pathway

FCX‐146, a potent allosteric inhibitor of Akt kinase in cancer cells: Lead optimization of the second‐generation arylidene indanone scaffold

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