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A novel quinazolinone derivative induces cytochrome c interdependent apoptosis and autophagy in human leukemia MOLT-4 cells.

ABSTRACT: Crosstalk between apoptosis and autophagy is budding as one of the novel strategies in the cancer therapeutics. The present study tinted toward the interdependence of autophagy and apoptosis induce by a novel quinazolinone derivative 2,3-dihydro-2-(quinoline-5-yl) quinazolin-4(1H)-one structure [DQQ] in human leukemia MOLT-4 cells. DQQ induces cytochrome c arbitrated apoptosis and autophagy in MOLT-4 cells. Apoptosis induces by DQQ was confirmed through a battery of assay e.g. cellular and nuclear microscopy, annexin-V assay, cell cycle analysis, loss of mitochondrial membrane potential and immune-expression of cytochrome c, caspases and PARP. Furthermore, acridine orange staining, LC3 immunofluorescence and western blotting of key autophagy proteins revealed the autophagic potential of DQQ. A universal caspase inhibitor, Z-VAD-FMK and cytochrome c silencing, strongly inhibited the DQQ induce autophagy and apoptosis. Beclin1 silencing through siRNA partially reversed the cell death, which was not as significant as by cytochrome c silencing. Although, it partially reversed the PARP cleavage induced by DQQ, indicating the role of autophagy in the regulation of apoptosis. The present study first time portrays the negative feedback potential of cytochrome c regulated autophagy and the importance of quinazolinone derivative in discovery of novel anticancer therapeutics.

SUBMITTER: Kumar S

PROVIDER: S-EPMC5598135 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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A novel quinazolinone derivative induces cytochrome c interdependent apoptosis and autophagy in human leukemia MOLT-4 cells.

Kumar Suresh S Guru Santosh Kumar SK Pathania Anup Singh AS Mupparapu Nagaraju N Kumar Ajay A Malik Fayaz F Bharate Sandip B SB Naveed Ahmed Qazi Q Vishwakarma Ram A RA Bhushan Shashi S

Toxicology reports 20140812

Crosstalk between apoptosis and autophagy is budding as one of the novel strategies in the cancer therapeutics. The present study tinted toward the interdependence of autophagy and apoptosis induce by a novel quinazolinone derivative 2,3-dihydro-2-(quinoline-5-yl) quinazolin-4(1H)-one structure [DQQ] in human leukemia MOLT-4 cells. DQQ induces cytochrome c arbitrated apoptosis and autophagy in MOLT-4 cells. Apoptosis induces by DQQ was confirmed through a battery of assay e.g. cell ...[more]

PMID: 28962314

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Project description:Novel quinazolinone compounds have been studied in the field of drug discovery for a long time. Among their broad range of pharmacological effects, certain compounds effectively inhibit cancer cell proliferation. MJ?33 is a quinazolinone derivative with proposed anticancer activities that was synthesized in our laboratory. The present study aimed to evaluate the anticancer activity of MJ?33 in fluorouracil (5FU)?resistant colorectal cancer cells (HT?29/5FUR) and to investigate the underlying molecular mechanisms. The cell viability assay results indicated that HT?29/5FUR cell viability was inhibited by MJ?33 treatment in a concentration?dependent manner compared with the control group. The cellular morphological alterations observed following MJ?33 treatment indicated the occurrence of apoptosis and autophagy, as well as inhibition of cell proliferation in a time?dependent manner compared with the control group. The acridine orange, LysoTracker Red and LC3?green fluorescent protein staining results indicated that MJ?33 treatment significantly induced autophagy compared with the control group. The DAPI/TUNEL dual staining results demonstrated increased nuclear fragmentation and condensation following MJ?33 treatment compared with the control group. The Annexin V apoptosis assay and image cytometry analysis results demonstrated a significant increase in apoptotic cells following MJ?33 treatment compared with the control group. The western blotting results demonstrated markedly decreased Bcl?2, phosphorylated (p)?BAD, pro?caspase?9 and pro?caspase?3 expression levels, and notably increased cytochrome c and apoptotic peptidase activating factor 1 expression levels following MJ?33 treatment compared with the control group. Moreover, the expression levels of autophagy?related proteins, including autophagy related (ATG)?5, ATG?7, ATG?12, ATG?16, p62 and LC3?II, were increased following MJ?33 treatment compared with the control group. Furthermore, MJ?33?treated HT?29/5FUR cells displayed decreased expression levels of p?AKT and p?mTOR compared with control cells. The results suggested that MJ?33?induced apoptosis was mediated by AKT signaling, and subsequently modulated via the mitochondria?dependent signaling pathway. Therefore, the results suggested that suppression of AKT/mTOR activity triggered autophagy in the HT?29/5FUR cell line. In summary, the results indicated that MJ?33 inhibited HT?29/5FUR cell viability, and induced apoptosis and autophagy via the AKT/mTOR signaling pathway. The present study may provide novel insight into the anticancer effects and mechanisms underlying MJ?33 in 5FU?resistant colorectal cancer cells.

Project description:AimPhyscion is a major bioactive ingredient in the traditional Chinese medicine Radix et Rhizoma Rhei, which has an anthraquinone chemical structure and exhibits a variety of pharmacological activities including laxative, hepatoprotective, anti-inflammatory, anti-microbial and anti-proliferative effects. In this study we investigated the effect of physcion on human nasopharyngeal carcinoma in vitro and in vivo, as well as the mechanisms underlying the anti-tumor action.MethodsThe nasopharyngeal carcinoma cell line CNE2 was treated with physcion, and cell viability was detected using MTT and colony formation assays. Flow cytometry was used to assess the cell cycle arrest, mitochondrial membrane potential loss, apoptosis, autophagy and intracellular ROS generation. Apoptotic cell death was also confirmed by a TUNEL assay. The expression of target or marker molecules was determined using Western blotting. The activity of caspase-3, 8, and 9 was detected with an ELISA kit. A xenograft murine model was used to evaluate the in vivo anti-tumor action of physcion, the mice were administered physcion (10, 20 mg·kg-1·d-1, ip) for 30 d.ResultsTreatment with physcion (5, 10, and 20 μmol/L) dose-dependently suppressed the cell viability and colony formation in CNE2 cells. Physcion (10 and 20 μmol/L) dose-dependently blocked cell cycle progression at G1 phase and induced both caspase-dependent apoptosis and autophagy in CNE2 cells. Furthermore, physcion treatment induced excessive ROS generation in CNE2 cells, and subsequently disrupted the miR-27a/ZBTB10 axis, resulting in repression of the transcription factor Sp1 that was involved in physcion-induced apoptosis and autophagy. Moreover, physcion-induced autophagy acted as a pro-apoptotic factor, and possibly contributed to physcion-induced apoptosis. In the xenograft murine model, administration of physcion dose-dependently suppressed the tumor growth without affecting the body weight. Furthermore, the anti-tumor effects of physcion were correlated with downregulation of Sp1 and suppression of miR-27a in the tumor tissues.ConclusionPhyscion induces apoptosis and autophagy in human nasopharyngeal carcinoma by targeting Sp1, which was mediated by ROS/miR-27a/ZBTB10 signaling. The results suggest that physcion is a promising candidate for the treatment of human nasopharyngeal carcinoma.

Project description:Molt-4 leukemia cells undergo p53-dependent apoptosis accompanied by accumulation of de novo ceramide after 14 hours of ?-irradiation. In order to identify the potential mediators involved in ceramide accumulation and the cell death response, differentially expressed genes were identified by Affymetrix Microarray Analysis. Molt-4-LXSN cells, expressing wild type p53, and p53-deficient Molt-4-E6 cells were irradiated and harvested at 3 and 8 hours post-irradiation. Human genome U133 plus 2.0 array containing >47,000 transcripts was used for gene expression profiling. From over 10,000 probes, 281 and 12 probes were differentially expressed in Molt-4-LXSN and Molt-4-E6 cells, respectively. Data analysis revealed 63 (upregulated) and 20 (downregulated) genes (>2 fold) in Molt-4-LXSN at 3 hours and 140 (upregulated) and 21 (downregulated) at 8 hours post-irradiation. In Molt-4-E6 cells, 5 (upregulated) genes each were found at 3 hours and 8 hours, respectively. In Molt-4-LXSN cells, a significant fraction of the genes with altered expression at 3 hours were found to be involved in apoptosis signaling pathway (BCL2L11), p53 pathway (PMAIP1, CDKN1A and FAS) and oxidative stress response (FDXR, CROT and JUN). Similarly, at 8 hours the genes with altered expression were involved in the apoptosis signaling pathway (BAX, BIK and JUN), p53 pathway (BAX, CDKN1A and FAS), oxidative stress response (FDXR and CROT) and p53 pathway feedback loops 2 (MDM2 and CDKN1A). A global molecular and biological interaction map analysis showed an association of these altered genes with apoptosis, senescence, DNA damage, oxidative stress, cell cycle arrest and caspase activation. In a targeted study, activation of apoptosis correlated with changes in gene expression of some of the above genes and revealed sequential activation of both intrinsic and extrinsic apoptotic pathways that precede ceramide accumulation and subsequent execution of apoptosis. One or more of these altered genes may be involved in p53-dependent ceramide accumulation.

Dataset Information

A novel quinazolinone derivative induces cytochrome c interdependent apoptosis and autophagy in human leukemia MOLT-4 cells.

Publications

A novel quinazolinone derivative induces cytochrome <i>c</i> interdependent apoptosis and autophagy in human leukemia MOLT-4 cells.

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