Browsing by Subject "Apoptosis"
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Item 4-(4-Chloro-2-methylphenoxy)-N-hydroxybutanamide (CMH) targets mRNA of the c-FLIP variants and induces apoptosis in MCF-7 human breast cancer cells(Springer US, 2010-09) Bijangi-Vishehsaraei, Khadijeh; Huang, Su; Safa, Ahmad R.; Saadatzadeh, Mohammad Reza; Murphy, Michael P.; Department of Pharmacology & Toxicology, School of MedicineCellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) is a major resistance factor for the tumor necrosis factor-related apoptosis-inducing ligand TRAIL and in drug resistance in human malignancies. c-FLIP is an antagonist of caspases-8 and -10, which inhibits apoptosis and is expressed as long (c-FLIPL) and short (c-FLIPS) splice forms. c-FLIP is often overexpressed in various human cancers, including breast cancer. Several studies have shown that silencing c-FLIP by specific siRNAs sensitizes cancer cells to TRAIL and anticancer agents. However, systemic use of siRNA as a therapeutic agent is not practical at present. In order to reduce or inhibit c-FLIP expression, small molecules are needed to allow targeting c-FLIP without inhibiting caspases-8 and -10. We used a small molecule inhibitor of c-FLIP, 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide (CMH), and show that CMH, but not its inactive analog, downregulated c-FLIPL and c-FLIPS mRNA and protein levels, caused poly(ADP-ribose) polymerase (PARP) degradation, reduced cell survival, and induced apoptosis in MCF-7 breast cancer cells. These results revealed that c-FLIP is a critical apoptosis regulator that can serve as a target for small molecule inhibitors that downregulate its expression and serve as effective targeted therapeutics against breast cancer cells.Item Aglianico Grape Seed Semi-Polar Extract Exerts Anticancer Effects by Modulating MDM2 Expression and Metabolic Pathways(MDPI, 2023-01-04) Cuciniello, Rossana; Di Meo, Francesco; Sulli, Maria; Demurtas, Olivia Costantina; Tanori, Mirella; Mancuso, Mariateresa; Villano, Clizia; Aversano, Riccardo; Carputo, Domenico; Baldi, Alfonso; Diretto, Gianfranco; Filosa, Stefania; Crispi, Stefania; Medicine, School of MedicineGrapevine (Vitis vinifera L.) seeds are rich in polyphenols including proanthocyanidins, molecules with a variety of biological effects including anticancer action. We have previously reported that the grape seed semi-polar extract of Aglianico cultivar (AGS) was able to induce apoptosis and decrease cancer properties in different mesothelioma cell lines. Concomitantly, this extract resulted in enriched oligomeric proanthocyanidins which might be involved in determining the anticancer activity. Through transcriptomic and metabolomic analyses, we investigated in detail the anticancer pathway induced by AGS. Transcriptomics analysis and functional annotation allowed the identification of the relevant causative genes involved in the apoptotic induction following AGS treatment. Subsequent biological validation strengthened the hypothesis that MDM2 could be the molecular target of AGS and that it could act in both a p53-dependent and independent manner. Finally, AGS significantly inhibited tumor progression in a xenograft mouse model of mesothelioma, confirming also in vivo that MDM2 could act as molecular player responsible for the AGS antitumor effect. Our findings indicated that AGS, exerting a pro-apoptotic effect by hindering MDM2 pathway, could represent a novel source of anticancer molecules.Item Anticancer effect of Moringa oleifera leaves extract against lung cancer cell line via induction of apoptosis(Elsevier, 2022-12) Bhadresha, Kinjal; Thakore, Vaidehi; Brahmbhatt, Jpan; Upadhyay, Vinal; Jain, Nayan; Rawal, Rakesh; Medicine, School of MedicineSince ancient times, Moringa oleifera has been a common vegetable in many nations. It has a large number of phenolic compounds with a diverse range of biological activity. It has anticancer properties that can be exploited to create novel medications for the treatment of various malignancies. The current study was conducted to evaluate the in vitro anticancer activities of M. oleifera leaves extracts. The M. oleifera leaves extracts significantly inhibited cell proliferation in the human cancer cell line A549 in a dose-dependent manner. Morphological studies indicated that the extract of moringa leaves stimulated apoptosis as demonstrated by cell shrinkage, blebbing, chromatin condensation, and nuclear fragmentation. Quantitative RT-PCR analyses of Bax and Bcl-2 showed abnormal expression profiles of these genes under various treatment conditions. This study demonstrates that M. oleifera leaves may have the ability to suppress the growth of cancer cells while also enhancing human health and developing new food ingredients. The phytochemicals from M. oleifera leaves can be employed as the primary medications to cure cancer, according to in vitro studies.Item Anticancer effect of Moringa oleifera leaves extract against lung cancer cell line via induction of apoptosis(Elsevier, 2022) Bhadresha, Kinjal; Thakore, Vaidehi; Brahmbhatt, Jpan; Upadhyay, Vinal; Jain, Nayan; Rawal, Rakesh; Medicine, School of MedicineSince ancient times, Moringa oleifera has been a common vegetable in many nations. It has a large number of phenolic compounds with a diverse range of biological activity. It has anticancer properties that can be exploited to create novel medications for the treatment of various malignancies. The current study was conducted to evaluate the in vitro anticancer activities of M. oleifera leaves extracts. The M. oleifera leaves extracts significantly inhibited cell proliferation in the human cancer cell line A549 in a dose-dependent manner. Morphological studies indicated that the extract of moringa leaves stimulated apoptosis as demonstrated by cell shrinkage, blebbing, chromatin condensation, and nuclear fragmentation. Quantitative RT-PCR analyses of Bax and Bcl-2 showed abnormal expression profiles of these genes under various treatment conditions. This study demonstrates that M. oleifera leaves may have the ability to suppress the growth of cancer cells while also enhancing human health and developing new food ingredients. The phytochemicals from M. oleifera leaves can be employed as the primary medications to cure cancer, according to in vitro studies.Item Apoptotic osteocytes and the control of targeted bone resorption(Springer US, 2014-03) Plotkin, Lilian I.; Department of Anatomy & Cell Biology, IU School of MedicineStudies from the 1950s and 1960s already recognize the fact that osteocytes, although long living cells, die, as evidenced by accumulation of osteocytic lacunae devoid of cells. More recently, it was demonstrated that these cells die by apoptosis. The rate of osteocyte apoptosis is regulated by the age of the bone, as well as by systemic hormones, local growth factors, cytokines, pharmacological agents, and mechanical forces. Apoptotic osteocytes, in turn, recruit osteoclasts to initiate targeted bone resorption. This results in the removal of “dead” bone and may improve the mechanical properties of the skeleton. However, the molecular regulators of osteocyte survival and targeted bone remodeling are not completely known. In this review, the current knowledge on the molecular mechanism that lead to osteocyte death or survival, and the signals that mediate targeted bone resorption is discussed.Item ATF4 regulates arsenic trioxide-mediated NADPH oxidase, ER-mitochondrial crosstalk and apoptosis(Elsevier, 2016-11-01) Srivastava, Ritesh K; Li, Changzhao; Ahmad, Aftab; Abrams, Onika; Gorbatyuk, Marina S.; Harrod, Kevin S.; Wek, Ronald C.; Afaq, Farrukh; Athar, Mohammad; Biochemistry and Molecular Biology, School of MedicineArsenic is a mitochondrial toxin, and its derivatives, such as arsenic trioxide (ATO), can trigger endoplasmic reticulum (ER) and the associated unfolded protein response (UPR). Here, we show that arsenic induction of the UPR triggers ATF4, which is involved in regulating this ER-mitochondrial crosstalk that is important for the molecular pathogenesis of arsenic toxicity. Employing ATF4+/+ and ATF4−/− MEFs, we show that ATO induces UPR and impairs mitochondrial integrity in ATF4+/+ MEF cells which is largely ablated upon loss of ATF4. Following ATO treatment, ATF4 activates NADPH oxidase by promoting assembly of the enzyme components Rac-1/P47phox/P67phox, which generates ROS/superoxides. Furthermore, ATF4 is required for triggering Ca++/calpain/caspase-12-mediated apoptosis following ATO treatment. The IP3R inhibitor attenuates Ca++/calpain-dependent apoptosis, as well as reduces m-ROS and MMP disruption, suggesting that ER-mitochondria crosstalk involves IP3R-regulated Ca++ signaling. Blockade of m-Ca++ entry by inhibiting m-VDAC reduces ATO-mediated UPR in ATF4+/+ cells. Additionally, ATO treatment leads to p53-regulated mitochondrial apoptosis, where p53 phosphorylation plays a key role. Together, these findings indicate that ATO-mediated apoptosis is regulated by both ER and mitochondria events that are facilitated by ATF4 and the UPR. Thus, we describe novel mechanisms by which ATO orchestrates cytotoxic responses involving interplay of ER and mitochondria.,Item Augmented Concentration of Isopentyl-Deoxynyboquinone in Tumors Selectively Kills NAD(P)H Quinone Oxidoreductase 1-Positive Cancer Cells through Programmed Necrotic and Apoptotic Mechanisms(MDPI, 2023-12-14) Wang, Jiangwei; Su, Xiaolin; Jiang, Lingxiang; Boudreau, Matthew W.; Chatkewitz, Lindsay E.; Kilgore, Jessica A.; Zahid, Kashif Rafiq; Williams, Noelle S.; Chen, Yaomin; Liu, Shaohui; Hergenrother, Paul J.; Huang, Xiumei; Biochemistry and Molecular Biology, School of MedicineLung and breast cancers rank as two of the most common and lethal tumors, accounting for a substantial number of cancer-related deaths worldwide. While the past two decades have witnessed promising progress in tumor therapy, developing targeted tumor therapies continues to pose a significant challenge. NAD(P)H quinone oxidoreductase 1 (NQO1), a two-electron reductase, has been reported as a promising therapeutic target across various solid tumors. β-Lapachone (β-Lap) and deoxynyboquinone (DNQ) are two NQO1 bioactivatable drugs that have demonstrated potent antitumor effects. However, their curative efficacy has been constrained by adverse effects and moderate lethality. To enhance the curative potential of NQO1 bioactivatable drugs, we developed a novel DNQ derivative termed isopentyl-deoxynyboquinone (IP-DNQ). Our study revealed that IP-DNQ treatment significantly increased reactive oxygen species generation, leading to double-strand break (DSB) formation, PARP1 hyperactivation, and catastrophic energy loss. Notably, we discovered that this novel drug induced both apoptosis and programmed necrosis events, which makes it entirely distinct from other NQO1 bioactivatable drugs. Furthermore, IP-DNQ monotherapy demonstrated significant antitumor efficacy and extended mice survival in A549 orthotopic xenograft models. Lastly, we identified that in mice IP-DNQ levels were significantly elevated in the plasma and tumor compared with IB-DNQ levels. This study provides novel preclinical evidence supporting IP-DNQ efficacy in NQO1+ NSCLC and breast cancer cells.Item Avenanthramides Prevent Osteoblast and Osteocyte Apoptosis and Induce Osteoclast Apoptosis in Vitro in an Nrf2-Independent Manner(MDPI, 2016-07-11) Pellegrini, Gretel G.; Morales, Cynthya C.; Wallace, Taylor C.; Plotkin, Lilian I.; Bellido, Teresita; Department of Anatomy & Cell Biology, IU School of MedicineOats contain unique bioactive compounds known as avenanthramides (AVAs) with antioxidant properties. AVAs might enhance the endogenous antioxidant cellular response by activation of the transcription factor Nrf2. Accumulation of reactive oxygen species plays a critical role in many chronic and degenerative diseases, including osteoporosis. In this disease, there is an imbalance between bone formation by osteoblasts and bone resorption by osteoclasts, which is accompanied by increased osteoblast/osteocyte apoptosis and decreased osteoclast apoptosis. We investigated the ability of the synthethic AVAs 2c, 2f and 2p, to 1-regulate gene expression in bone cells, 2-affect the viability of osteoblasts, osteocytes and osteoclasts, and the generation of osteoclasts from their precursors, and 3-examine the potential involvement of the transcription factor Nrf2 in these actions. All doses of AVA 2c and 1 and 5 µM dose of 2p up-regulated collagen 1A expression. Lower doses of AVAs up-regulated OPG (osteoprotegerin) in OB-6 osteoblastic cells, whereas 100 μM dose of 2f and all concentrations of 2c down-regulated RANKL gene expression in MLO-Y4 osteocytic cells. AVAs did not affect apoptosis of OB-6 osteoblastic cells or MLO-Y4 osteocytic cells; however, they prevented apoptosis induced by the DNA topoisomerase inhibitor etoposide, the glucocorticoid dexamethasone, and hydrogen peroxide. AVAs prevented apoptosis of both wild type (WT) and Nrf2 Knockout (KO) osteoblasts, demonstrating that AVAs-induced survival does not require Nrf2 expression. Further, KO osteoclast precursors produced more mature osteoclasts than WT; and KO cultures exhibited less apoptotic osteoclasts than WT cultures. Although AVAs did not affect WT osteoclasts, AVA 2p reversed the low apoptosis of KO osteoclasts. These in vitro results demonstrate that AVAs regulate, in part, the function of osteoblasts and osteocytes and prevent osteoblast/osteocyte apoptosis and increase osteoclast apoptosis; further, these regulatory actions are independent of Nrf2.Item BID mediates selective killing of APC-deficient cells in intestinal tumor suppression by nonsteroidal antiinflammatory drugs(PNAS, 2014-11-18) Leibowitz, Brian; Qiu, Wei; Buchanan, Monica E.; Zou, Fangdong; Vernon, Philip; Moyer, Mary P.; Yin, Xiao-Ming; Schoen, Robert E.; Yu, Jian; Zhang, Lin; Department of Pathology and Laboratory Medicine, IU School of MedicineColorectal tumorigenesis is driven by genetic alterations in the adenomatous polyposis coli (APC) tumor suppressor pathway and effectively inhibited by nonsteroidal antiinflammatory drugs (NSAIDs). However, how NSAIDs prevent colorectal tumorigenesis has remained obscure. We found that the extrinsic apoptotic pathway and the BH3 interacting-domain death agonist (BID) are activated in adenomas from NSAID-treated patients. Loss of BID abolishes NSAID-mediated tumor suppression, survival benefit, and apoptosis in tumor-initiating stem cells in APC(Min/+) mice. BID-mediated cross-talk between the extrinsic and intrinsic apoptotic pathways is responsible for selective killing of neoplastic cells by NSAIDs. We further demonstrate that NSAIDs induce death receptor signaling in both cancer and normal cells, but only activate BID in cells with APC deficiency and ensuing c-Myc activation. Our results suggest that NSAIDs suppress intestinal tumorigenesis through BID-mediated synthetic lethality triggered by death receptor signaling and gatekeeper mutations, and provide a rationale for developing more effective cancer prevention strategies and agents.Item Bidirectional Notch signaling and osteocyte-derived factors in the bone marrow microenvironment promote tumor cell proliferation and bone destruction in multiple myeloma(American Association for Cancer Research, 2016-03-01) Delgado-Calle, Jesus; Anderson, Judith; Cregor, Meloney D.; Hiasa, Masahiro; Chirgwin, John M.; Carlesso, Nadia; Yoneda, Toshiyuki; Mohammad, Khalid S.; Plotkin, Lilian I.; Roodman, G. David; Bellido, Teresita; Department of Anatomy & Cell Biology, IU School of MedicineIn multiple myeloma, an overabundance of monoclonal plasma cells in the bone marrow induces localized osteolytic lesions that rarely heal due to increased bone resorption and suppressed bone formation. Matrix-embedded osteocytes comprise more than 95% of bone cells and are major regulators of osteoclast and osteoblast activity, but their contribution to multiple myeloma growth and bone disease is unknown. Here, we report that osteocytes in a mouse model of human MM physically interact with multiple myeloma cells in vivo, undergo caspase-3-dependent apoptosis, and express higher RANKL (TNFSF11) and sclerostin levels than osteocytes in control mice. Mechanistic studies revealed that osteocyte apoptosis was initiated by multiple myeloma cell-mediated activation of Notch signaling and was further amplified by multiple myeloma cell-secreted TNF. The induction of apoptosis increased osteocytic Rankl expression, the osteocytic Rankl/Opg (TNFRSF11B) ratio, and the ability of osteocytes to attract osteoclast precursors to induce local bone resorption. Furthermore, osteocytes in contact with multiple myeloma cells expressed high levels of Sost/sclerostin, leading to a reduction in Wnt signaling and subsequent inhibition of osteoblast differentiation. Importantly, direct contact between osteocytes and multiple myeloma cells reciprocally activated Notch signaling and increased Notch receptor expression, particularly Notch3 and 4, stimulating multiple myeloma cell growth. These studies reveal a previously unknown role for bidirectional Notch signaling that enhances MM growth and bone disease, suggesting that targeting osteocyte-multiple myeloma cell interactions through specific Notch receptor blockade may represent a promising treatment strategy in multiple myeloma.