350 research outputs found
Abstract 4422: Capsaicin suppresses pancreatic tumor growth by inhibiting tumor cell metabolism
No full textAbstract
Tumor cell metabolism is considered to be a hallmark of tumorigenic progression. Pancreatic cancer cells are shown to develop addiction towards the metabolic pathways like glycolysis and mitochondrial respiration to meet energy demands. Pancreatic tumor cells predominantly utilize cytosolic aerobic glycolysis for energy production. In our previous studies, we have reported that capsaicin treatment inhibits the survival of AsPC-1 and BxPC-3 pancreatic cancer cell lines. In this study, we evaluated the effect of capsaicin on glycolysis and mitochondrial respiration in pancreatic cancer cells. Our results showed that capsaicin treatment reduced the extra-cellular acidification rate (glycolysis) and oxygen consumption rate (mitochondrial respiration) in AsPC-1 and BxPC-3 cells in a concentration-dependent manner after 24h of treatment. Capsaicin treatment caused 86% and 55% down-regulation of glycolysis process in AsPC-1and BxPC-3 cells respectively. Our results also indicate the inhibition of glycolytic capacity and glycolytic reserve by capsaicin treatment indicating the potential of capsaicin to inhibit glycolysis. In addition, capsaicin treatment reduced 98% of basal oxygen consumption rate and ATP production in AsPC-1 cells. Furthermore, capsaicin treatment inhibited spare respiratory capacity & proton leak in a concentration dependent manner in AsPC-1 cells. Treatment of AsPC-1 and BxPC-3 with capsaicin for 48h also inhibited the expression of LDH-A and its upstream regulators such as HIF-1α, pSTAT3 (Y705) and EGFR as evaluated by Western blot. Our study thus indicate that capsaicin suppresses pancreatic tumor growth by down-regulating glycolysis and mitochondrial respiration. Further mechanistic studies are in progress. [Supported in part by R01 grant CA129038, awarded to (S.K.S.) by the National Cancer Institute].
Citation Format: Sharavan Ramachandran, Sanjay K. Srivastava. Capsaicin suppresses pancreatic tumor growth by inhibiting tumor cell metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4422. doi:10.1158/1538-7445.AM2017-4422</jats:p
Abstract 4508: Penfluridol-induced endoplasmic reticulum stress leads to autophagy-mediated pancreatic tumor growth suppression
No full textAbstract
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States. Experimental and clinical evidences suggested that high basal state autophagy in pancreatic tumors could induce resistance to chemotherapies. Recently, we have demonstrated that penfluridol suppresses pancreatic tumor growth by autophagy-mediated apoptosis both in vitro and in vivo. (Ranjan and Srivastava, Scientific Reports: 2016;6:26165; PMID: 27189859), however the mechanism of autophagy induction by penfluridol was not clear. Several studies have established that endoplasmic reticulum (ER) stress could lead to autophagy and inhibit tumor progression. In the current study, we demonstrated that penfluridol induced ER stress in BxPC-3, AsPC-1 and Panc-1, pancreatic cancer cell lines as indicated by up regulation of ER stress markers such as BIP, CHOP and IRE1α after treatment with penfluridol in a concentration-dependent manner. Inhibiting ER stress by pre-treatment with pharmacological inhibitors such as sodium phenylbutyrate and mithramycin or by silencing CHOP using CHOPsiRNA, blocked penfluridol-induced autophagy. These results clearly indicated that penfluridol induced ER stress lead to autophagy in our model. Western blot analysis of subcutaneously implanted AsPC-1 and BxPC-3 tumors as well as orthotopically implanted Panc-1 tumors demonstrated upregulation of BIP, CHOP and IRE1α expression in the tumors lysates from penfluridol treated mice as compared to tumors from control mice. Altogether, our study established that penfluridol induced ER stress mediated autophagy in pancreatic tumor. Our study opened a new therapeutic target for advanced chemotherapies against pancreatic cancer. (Supported in part by RO1 grant CA129038, awarded by National Cancer Institute, NIH).
Citation Format: Alok Ranjan, Sharavan Ramachandran, Nehal Gupta, Sanjay Srivastava. Penfluridol-induced endoplasmic reticulum stress leads to autophagy-mediated pancreatic tumor growth suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4508. doi:10.1158/1538-7445.AM2017-4508</jats:p
Abstract 1666: Immune consequences of penfluridol treatment associated with inhibition of glioblastoma tumor growth
No full textAbstract
Glioblastoma is the most common and lethal brain tumor associated with only 12% median survival rate of patients. Despite the development of advanced surgical, radiation or use of combinations of anti-cancer drugs, treatment for glioblastoma patients is still a challenge. The major contributing factor in glioblastoma progression and resistive nature is its ability to evade the immune surveillance. Hence, modulating the immune system in glioblastoma tumors could be an important strategy for anticancer therapeutics. Penfluridol, an antipsychotic drug has been shown to have anti-cancer properties in our recently published studies. The present study evaluates the immune response of penfluridol in glioblastoma tumors. Our results demonstrated that penfluridol treatment significantly suppressed glioblastoma tumor growth. Our current results demonstrated about 72% suppression of myeloid derived suppressor cells (MDSCs) with penfluridol treatment in mouse bearing U87MG glioblastoma tumors. MDSCs are known to increase regulatory T cells (Treg), which are immunosuppressive in nature and suppresses M1 macrophages that are tumor suppressive in nature. Our results also showed suppression of regulatory T cells as well as elevation of M1 macrophages with penfluridol treatment by 58% and 57% respectively. Decrease in CCL4 as well as IFNγ with penfluridol treatment was also observed indicating decrease in overall tumor inflammation. This is the first report demonstrating immune modulations by penfluridol treatment associated with glioblastoma tumor growth suppression prompting further investigation to establish penfluridol as a treatment option for glioblastoma patients. [Studies supported in part by R01 grant CA129038, awarded by National Cancer Institute, NIH]
Citation Format: Alok Ranjan, Nehal Gupta, Sharavan Ramachandran, Stephen Wright, Sanjay Srivastava. Immune consequences of penfluridol treatment associated with inhibition of glioblastoma tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1666. doi:10.1158/1538-7445.AM2017-1666</jats:p
Immunocytochemical staining of Drosophila larval body-wall muscles
No full textFirst author Preethi Ramachandran is a doctoral student in the Neuroscience Program in the Morningside Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.Over the last two decades, the Drosophila larval neuromuscular junction (NMJ) has gained immense popularity as a model system for the study of synaptic development, function, and plasticity. With this model, it is easy to visualize synapses and manipulate the system genetically with a high degree of temporal and spatial control, which makes it ideal for resolving problems in synaptic physiology and development. This article describes a procedure for labeling various proteins with antibodies in dissected larval body-wall muscles and visualizing their localization and distribution in the brain, NMJ, and muscle.Neuroscienc
Dissection of Drosophila larval body-wall muscles
No full textFirst author Preethi Ramachandran is a doctoral student in the Neuroscience Program in the Morningside Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.Over the last two decades, the Drosophila larval neuromuscular junction has gained immense popularity as a model system for the study of synaptic development, function, and plasticity. With this model, it is easy to visualize synapses and manipulate the system genetically with a high degree of temporal and spatial control, which makes it ideal for resolving problems in synaptic physiology and development. A number of different techniques have been used to dissect third-instar larval preparations to expose the body-wall muscles. Here, we describe a procedure that uses magnetic chambers and pins to allow for fine control in spreading the larval body wall.Neuroscienc
Repurposing pimavanserin, an antipsychotic drug for pancreatic cancer and medulloblastoma treatment
No full textCancer has been known to exist for several hundreds of years and has become one of the deadliest diseases as witnessed by mankind. Currently, cancer is the second leading cause of death after cardiovascular disease. Amongst several cancer subtypes, pancreatic ductal adenocarcinoma (PDAC) and Medulloblastoma (MB) are identified as some of the deadlier cancers with high mortality rate in adults and children respectively. Tumor relapse after surgery, chemoresistance and resistance to radiation therapy have hampered the management of cancer. In the context of MB, penetration of drugs through the blood brain barrier is a bottleneck for the treatment of MB. In spite of the initial effective treatment, PDAC and MB cells develop resistance to therapy due to mutations. Genetic mutations lead to inactivation of tumor suppressor genes and constitutive activation of oncogenic signaling pathways, such as STAT3, PI3K/Akt, Src, Lyn, Hedgehog, EGFR and Cancer stem cells (CSCs) signaling. These obstacles warrant the need of novel drug developmental approaches to devise treatment options for PDAC and MB. Repurposing of existing non-cancer drugs like antipsychotic drugs has been proven to be effective against complex diseases including cancer. This dissertation elucidates the anti-cancer effects of an FDA approved antipsychotic drug, Pimavanserin in the in vitro and in vivo PDAC and MB models.
Several studies have demonstrated the tumorigenic role of Akt/Gli-1 regulated CSCs in various cancer models including PDAC. In the first project, our studies indicated that PVT induces apoptotic-mediated cell death in various PDAC cells and gemcitabine resistant cells by inhibiting Akt/Gli-1 signaling axis. Moreover, chronic administration of PVT suppressed the growth of subcutaneous and orthotopic PDAC, and gemcitabine resistant tumor xenografts with no major side effects.
Survival, initiation and progression of PDAC is partly supported by its high basal state autophagy. Nonetheless, several studies have demonstrated that inducing autophagy beyond its threshold causes apoptosis in PDAC cells. Our results demonstrated that PVT suppressed the growth of pancreatic tumors by inducing ULK1/autophagy-mediated apoptosis in the in vitro and in vivo models.
MB is one of the most lethal pediatric tumors which contributes to 20% of all childhood tumors. Lyn kinase and STAT3 signaling has been shown to mediate the survival of medulloblastoma stem cells and contribute to drug resistance. Our findings for the first time showed that, PVT treatment suppressed the growth of several MB cells by inhibiting the Lyn/STAT3/MBSC signaling axis. Furthermore, our studies showed that oral administration of PVT can suppress the growth of subcutaneous and intracranial MB tumor xenografts.
Taken together, our results demonstrated that PVT could serve as a novel therapeutic option for PDAC and MB. Given the remarkable preclinical efficacy of PVT and the availability of extensive toxicological and pharmacological information, our findings can accelerate the clinical development of PVT as an anti-cancer drug
Khoo Kay Kim, professor of Malaysian history : a biobibliometric study
No full textPresents an analysis of the publication productivity, authorship pattern, channels of communication, journal preference and language preference of Professor Dato' Khoo Kay Kim, Professor of Malaysian History in the University of Malaya, Kuala Lumpur. The results of this biobibliometric study indicate that he can be a role model for future Malaysian historians to emulate his various achievements especially in the field of history education
Biomechanical signals and the C-type natriuretic peptide counteract catabolic activities induced by IL-1? in chondrocyte/agarose constructs
No full textIntroduction: The present study examined the effect of C-type natriuretic peptide (CNP) on the anabolic and catabolic activities in chondrocyte/agarose constructs subjected to dynamic compression. Methods: Constructs were cultured under free-swelling conditions or subjected to dynamic compression with low (0.1 to 100 pM) or high concentrations (1 to 1,000 nM) of CNP, interleukin-1? (IL-1?), and/or KT-5823 (inhibits cyclic GMP-dependent protein kinase II (PKGII)). Anabolic and catabolic activities were assessed as follows: nitric oxide (NO) and prostaglandin E2 (PGE2) release, and [3H]-thymidine and 35SO4 incorporation were quantified by using biochemical assays. Gene expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), aggrecan, and collagen type II were assessed with real-time quantitative PCR (qPCR). Two-way ANOVA and the post hoc Bonferroni-corrected t tests were used to examine data. Results: CNP reduced NO and PGE2 release and partially restored [3H]-thymidine and 35SO4 incorporation in constructs cultured with IL-1?. The response was dependent on the concentration of CNP, such that 100 pM increased [3H]-thymidine incorporation (P < 0.001). This is in contrast to 35SO4 incorporation, which was enhanced with 100 or 1000 nM CNP in the presence and absence of IL-1? (P < 0.001). Stimulation by both dynamic compression and CNP and/or the PKGII inhibitor further reduced NO and PGE2 release and restored [3H]-thymidine and 35SO4 incorporation. In the presence and absence of IL-1?, the magnitude of stimulation for [3H]-thymidine and 35SO4 incorporation by dynamic compression was dependent on the concentration of CNP and the response was inhibited with the PKGII inhibitor. In addition, stimulation by CNP and/or dynamic compression reduced IL-1?-induced iNOS and COX-2 expression and restored aggrecan and collagen type II expression. The catabolic response was not further influenced with the PKGII inhibitor in IL-1?-treated constructs. Conclusions: Treatment with CNP and dynamic compression increased anabolic activities and blocked catabolic effects induced by IL-1?. The anabolic response was PKGII mediated and raises important questions about the molecular mechanisms of CNP with mechanical signals in cartilage. Therapeutic agents like CNP could be administered in conjunction with controlled exercise therapy to slow the OA disease progression and to repair damaged cartilage. The findings from this research provide the potential for developing novel agents to slow the pathophysiologic mechanisms and to treat OA in the young and old. <br/
Abstract 4807: Pimavanserin suppresses pancreatic tumor growth and resistance to gemcitabine by inhibiting Akt/Gli1 signaling
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