Quinazoline based small molecule exerts potent tumour suppressive properties by inhibiting PI3K/Akt/FoxO3a signalling in experimental colon cancer

Qazi, Asif Khurshid; Hussain, Aashiq; Khan, Sheema; Aga, Mushtaq A.; Behl, Akanksha; Ali, Shakir; Singh, Shashank; Taneja, Subhash C.; Shah, Bhahwal Ali; Saxena, Ajit Kumar; Mondhe, Dilip M.; Hamid, Abid

doi:10.1016/j.canlet.2014.12.034

Cited by 26 publications

(16 citation statements)

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“…The mTOR signaling pathway not only serves an important role in the growth and proliferation of normal cells, but is also associated with the process whereby normal cells become cancerous, as well as the growth and proliferation of cancer cells (28). In addition, it is involved in angiogenesis, and serves an important role in tumor formation, invasion and metastasis (28). In the present, the results demonstrated that wogonoside significantly suppressed p-mTOR protein expression in LOVO cells.…”

Section: Discussionsupporting

confidence: 53%

“…mTOR signaling pathway is essential to cell growth, as activated mTOR signaling pathway inhibits apoptosis induced by various stimuli, and promote cell cycle progression and cell survival and proliferation (27). The mTOR signaling pathway not only serves an important role in the growth and proliferation of normal cells, but is also associated with the process whereby normal cells become cancerous, as well as the growth and proliferation of cancer cells (28). In addition, it is involved in angiogenesis, and serves an important role in tumor formation, invasion and metastasis (28).…”

Section: Discussionmentioning

confidence: 99%

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Wogonoside inhibits cell growth and induces mitochondrial-mediated autophagy-related apoptosis in human colon cancer cells through the PI3K/AKT/mTOR/p70S6K signaling pathway

et al. 2018

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Abstract. Wogonoside, the main effective constituent of traditional Chinese medicine Scutellaria, belongs to the glucuronide family, with various functions, including detoxification, anti-inflammation and nourishing gallbladder, lowering blood pressure, diuresis and anti-allergic reactions. However, the effects of wogonoside on human colon cancer cells remain unclear. The present study aimed to investigate the anticancer effect of wogonoside on human colon cancer cells in vitro and its anticancer mechanisms. The results demonstrated that wogonoside significantly inhibited cell growth, induced apoptosis and mitochondrial-mediated autophagy of colon cancer cells. Furthermore, the results revealed that wogonoside significantly increased caspase-3 and caspase-9 expression levels, induced apoptosis regulator Bax/Bcl-2 and microtubule-associated protein 1A/1B-light chain 3 protein expression, suppressed the phosphatidylinositol 3 kinase (PI3K)/RAC-α serine/threonine-protein kinase (Akt)/mechanistic target of rapamycin (mTOR)/p70 S6 kinase (p70S6K) signaling pathway and induced p62 protein expression in colon cancer cells. In conclusion, these results demonstrated that wogonoside inhibits cell growth and induces mitochondrial mediated autophagy-related apoptosis in human colon cancer cells through modulation of the PI3K/Akt/mTOR/p70S6K signaling pathway.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Wogonoside inhibits cell growth and induces mitochondrial-mediated autophagy-related apoptosis in human colon cancer cells through the PI3K/AKT/mTOR/p70S6K signaling pathway

et al. 2018

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“…We report that the succinate-GPR91-PI3K/Akt axis also exists in the human heart. PI3K/AKT signaling plays major roles in the pathology of cancer and in the development of resistance in tumor cells [ 55 ], insulin resistance [ 56 ], and lung injury [ 57 ]. Therefore, many studies are needed to design a specific GPR91 inhibitor targeting this signaling pathway only in RVH.…”

Section: Discussionmentioning

confidence: 99%

The Succinate Receptor GPR91 Is Involved in Pressure Overload-Induced Ventricular Hypertrophy

Yang

et al. 2016

PLoS ONE

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BackgroundPulmonary arterial hypertension is characterized by increased pressure overload that leads to right ventricular hypertrophy (RVH). GPR91 is a formerly orphan G-protein-coupled receptor (GPCR) that has been characterized as a receptor for succinate; however, its role in RVH remains unknown.Methods and ResultsWe investigated the role of succinate-GPR91 signaling in a pulmonary arterial banding (PAB) model of RVH induced by pressure overload in SD rats. GPR91 was shown to be located in cardiomyocytes. In the sham and PAB rats, succinate treatment further aggravated RVH, up-regulated RVH-associated genes and increased p-Akt/t-Akt levels in vivo. In vitro, succinate treatment up-regulated the levels of the hypertrophic gene marker anp and p-Akt/t-Akt in cardiomyocytes. All these effects were inhibited by the PI3K antagonist wortmannin both in vivo and in vitro. Finally, we noted that the GPR91-PI3K/Akt axis was also up-regulated compared to that in human RVH.ConclusionsOur findings indicate that succinate-GPR91 signaling may be involved in RVH via PI3K/Akt signaling in vivo and in vitro. Therefore, GPR91 may be a novel therapeutic target for treating pressure overload-induced RVH.

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“…It induced nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB)-mediated apoptosis in human colon carcinoma HCT-116 cell lines [13] . A recent study, showed that its antiproliferative activity is through inhibition of PI3k/ Akt/FoxO3a pathway [14] .Although TAZQ has been studied extensively for its biological activities and is currently in pre-clinical studies as anticancer agent (with reference to personal communication with PK-PD Division, IIIM-CSIR, Jammu, India), its stability indicating assay method has …”

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confidence: 99%

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confidence: 99%

Stability-indicating HPLC Method for Determination of 7,8,9,10- tetrahydroazepino[2,1b]quinazolin-12(6H)-one, a Potential Anticancer Agent

Sharma¹,

Upadhyay²,

Mahindroo³

2016

pharmaceutical-sciences

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Sharma, et al.: Stability-indicating Method for Determination of a Potential Anticancer Agent 7,8,9,10-tetrahydroazepino[2,1b]quinazolin-12(6H)-one, a synthetic analog of vasicine, has been reported to be an anticancer, bronchodilator, antiinflammatory, antitussive, antiarthritic and antiasthamatic compound, which is under preclinical development for anticancer activity. The development of a validated reverse phase high performance liquid chromatography method is herein reported for the analysis and stability assessment. The analytical method was optimized using a C18 column and methanol:water (80:20 v/v) as mobile phase at flow rate of 0.9 ml/min. The eluents were monitored at 254 nm. Retention time of 7,8,9,10-tetrahydroazepino[2,1b]quinazolin-12(6H)-one was observed to be 3.9 min. It degraded significantly under alkaline conditions whereas negligible degradation was observed under acidic, oxidative, thermal and photolytic stress conditions. The peak of major degradation product, resulting from alkaline degradation, was well resolved from the peak of 7,8,9,10-tetrahydroazepino[2,1b]quinazolin-12(6H)-one. This method has been found to be linear, accurate, precise, robust, sensitive, specific, suitable and stability indicating.Key words: Quinazolines, cancer, HPLC, stability-indicating method 7,8,9,10-tetrahydroazepino[2,1b]quinazolin-12(6H)-one (TAZQ) ( fig. 1), a synthetic analog of vasicine, is currently under preclinical studies for anticancer activity. Vasicine is a major alkaloid obtained from the leaves of Adhatoda vasica Nees, a wellknown medicinal plant used in Ayurvedic and Unani medicine [1] . TAZQ has been extensively studied as bronchodilator [2][3][4][5][6][7] . It inhibited lung phosphodiesterase activity, lipooxygenase activity, histamine release and antigen-induced mast cell degranulation [8] . It showed synergistic antiasthamatic activity in combination with ambroxol in ovalbumin sensitized guinea pigs [5] . It showed antitussive activity in citric acid cough model in guinea pigs [9] . It's in vivo metabolic studies were performed in rhesus monkeys and Charles Foster rats.Various metabolites that were detected did not show any bronchodilatory activity [10,11] . TAZQ showed doserelated reduction in developing adjuvant arthritis in rats. It's LD 50 was lower than 1000 mg/kg p.o, thus was safe at pharmacologically active doses [12] . Structure activity relationship of TAZQ as bronchodilator has been studied extensively [7] . It induced nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB)-mediated apoptosis in human colon carcinoma HCT-116 cell lines [13] . A recent study, showed that its antiproliferative activity is through inhibition of PI3k/ Akt/FoxO3a pathway [14] .Although TAZQ has been studied extensively for its biological activities and is currently in pre-clinical studies as anticancer agent (with reference to personal communication with PK-PD Division, IIIM-CSIR, Jammu, India), its stability indicating assay method has

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Quinazoline based small molecule exerts potent tumour suppressive properties by inhibiting PI3K/Akt/FoxO3a signalling in experimental colon cancer

Cited by 26 publications

References 30 publications

Wogonoside inhibits cell growth and induces mitochondrial-mediated autophagy-related apoptosis in human colon cancer cells through the PI3K/AKT/mTOR/p70S6K signaling pathway

Wogonoside inhibits cell growth and induces mitochondrial-mediated autophagy-related apoptosis in human colon cancer cells through the PI3K/AKT/mTOR/p70S6K signaling pathway

The Succinate Receptor GPR91 Is Involved in Pressure Overload-Induced Ventricular Hypertrophy

Stability-indicating HPLC Method for Determination of 7,8,9,10- tetrahydroazepino[2,1b]quinazolin-12(6H)-one, a Potential Anticancer Agent

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