Browsing by Author "Mendonca, Marc"
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Item DCA and DMAPT as Radiosensitizing Drugs in the Treatment of Pancreatic Cancer(Office of the Vice Chancellor for Research, 2013-04-05) Cavazos, Ana; Mendonca, MarcPancreatic cancer is currently one of the deadliest forms of cancer. This is due to high local recurrence and invasiveness. Recurrence is thought to be due in part to the resistance of pancreatic cancer cells. Treatment for pancreatic cancer includes chemotherapy, radiation therapy and surgery. Currently, about 94% of all patients diagnosed with pancreatic cancer die within 5 years of diagnosis. Thus, the focus of this research is to develop a better therapeutic approach to therapy in order to improve the killing of cancer cells and prevent recurrence. We investigated two drugs, Dichloroacetate (DCA) and Dimethylaminoparthenolide (DMAPT, a derivative of Parthenolide). Both DCA and DMAPT were studied for their ability to radiosensitize and help increase radiation induced cell killing in drug treated cancer cells. The experiment involved pancreatic cancer cells (MIA PACA2) being exposed to DMAPT, DCA, and dual treatment, with or without radiation. The cells were then tested for survival rates and doubling times. The hypothesis is that DCA and DMAPT will enhance radiation-induced cell killing of MIA PACA2 cells. The results show that DMAPT and DCA are in fact toxic to the pancreatic cancer cell lines. The dual treatment suppressed cell growth, and increased doubling time of MIA PACA2 cells. Dual treatment also decreased the survival rate of the MIA PACA2 cells (depending on radiation dosage). The data shows that dual treatment of DCA and DMAPT radiation are beneficial in slowing down the spread of pancreatic cancer. Future research will study the mechanisms of radiation sensitization and could help to develop a new technique to treat pancreatic cancer.Item DMAPT AS A POTENTIAL RADIOSENSITIZER FOR PANCREATIC CANCER CELLS(Office of the Vice Chancellor for Research, 2012-04-13) Gill, Kiran; Mendonca, MarcPancreatic cancer is the fourth leading cause of cancer-related death in the United States with an estimated 37, 390 deaths expected to occur in 2012. The prognosis is very poor due to the recurrence and metastasis of the cancer with a 6% five-year survival rate for all stages combined. This study examined the effectiveness of dimethylamino-parthenolide (DMAPT) as a radiosensitizer to the human pancreatic cancer PaCa2 cell line. It is hypothe-sized that DMAPT, a bioavailable drug derived from parthenolide, will inhibit the activation of NF-κB and enhance radiation-induced cell killing of PaCa2 cells. NF-κB is a transcription factor that promotes cell survival, tumor pro-gression, and angiogenesis and reduces susceptibility to apoptosis. The re-sults show that DMAPT was toxic to the PaCa2 cell line. As a result, DMAPT suppressed cell growth and increased the doubling time of PaCa2 cells. The combination of 4μM DMAPT and radiation decreased cell survival. The PaCa2 cell line is radiosensitized by DMAPT but further investigation is required to determine the mechanism through which DMAPT works.Item Ionizing Radiation Affects Epigenetic Programming in Adolescent Mice(Office of the Vice Chancellor for Research, 2014-04-11) Watkins, Darryl S.; Mendonca, Marc; Lossie, Amy; Zhou, Feng C.Humans are exposed to low and mild doses of radiation frequently, ranging from the natural environment to medical procedures like x-ray and CT scans. Ionizing radiation of various doses has been known to potentially cause not only cellular but also genomic changes. Here, we demonstrate that epigenetics is also altered by the radiation. Epigenetics is a chemical coding above the gene, which plays critical roles in brain development, cognitive aberrations and other neurological impairments. How radiation, as an external environmental factor, causes epigenetic change is not understood. DNA methylation, key in epigenetics, including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) have been shown to either suppress or activate gene transcription. To aid in elucidating the role in which radiation affects epigenetic outcomes, we examined the effects of radiation on both epigenetic and phenotypic markers within the hippocampus. In this study we treated, via x-ray C57BL/6 mice, postnatal day (P) 21 with various doses (2Gy-4.5Gy) of radiation coupled with varying frequencies (0.5 Gy x 4, 1.5 Gy x 3, or 4.5Gy x 1) during a 4-week period. We used immunohistochemistry staining with cell proliferation, transcription and epigenetic markers. We found loss of 5mC in the sub-granular layer of the dentate gyrus (DG) in the upper and lower arms. Likewise a loss of 5hmC in the sub-granular layer of the DG, as well as in the cornu Ammonis (CA) layers 1 and 2. There was also loss of a transcriptional activation marker within the DG of the hippocampus. Furthermore, decreased cell proliferation in the adult neurogenesis in the hippocampus was found. Exposure to ionizing radiation altered the normal epigenetic profile of the mice. Understanding the mechanism by which ionizing radiation affects epigenetic programming will provide insight into how to develop protection against the potentially harmful risks associated with radiation exposure.Item Ionizing Radiation Affects Epigenetic Programming in Young Adult Mice(Office of the Vice Chancellor for Research, 2015-04-17) Watkins, Darryl S.; Mendonca, Marc; Lossie, Amy; Zhou, Feng C.Humans are exposed to low and mild doses of radiation frequently, ranging from the natural environment to medical procedures like x-ray and CT scans. Ionizing radiation of various doses has been known to cause not only cellular and genomic changes, but specific neurological systems such as the limbic system have been indicated to be particularly vulnerable. Here, we demonstrated that epigenetics is also altered by radiation. Epigenetics is a subtle chemical coding above the gene, which plays a critical role in brain development, and downstream can cause the onset of cognitive aberrations and other neurological impairments. How radiation as an external environmental factor causes epigenetic changes is not clearly understood. DNA methylation, including 5-methylcytosine (5M) and 5-hydroxymethylcytosine (5-hmC) have been shown to either suppress or activate gene transcription and as such are key epigenetic players. To elucidate the role of radiation in epigenetic outcomes, we examined epigenetic, phenotypic and transcriptional markers via immunohistochemistry, in the hippocampus and cortex. In this study C57BL/6 mouse (postnatal day 21 (P21)) began a 4-week radiation treatment of various doses totaling (2Gy-4.5Gy) via global head targeting CT exposure. We found a loss of 5M and 5-hmC as well as transcriptional markers within regions of the hippocampus and cortex. There was a significant decrease in cell proliferation in the hippocampus- specifically, in the region responsible for adult neurogenesis. The cingulate cortex (a region adjacent to the hippocampus) also exhibited dramatic alterations in several epigenetic and transcriptional markers, indicating the vulnerability of the limbic system in radiation exposure. Understanding the mechanism by which ionizing radiation affects epigenetic programming will provide insight into the transmissibility of external factors to biological systems. Additionally, this work can aid the development of protective strategies against the harmful risks associated with radiation exposure.Item Irradiation of Nf1 mutant mouse models of spinal plexiform neurofibromas drives pathologic progression and decreases survival(Oxford University Press, 2021-04-23) Laurent, Danny; Smith, Abbi E.; Bessler, Waylan K.; Mendonca, Marc; Chin-Sinex, Helen; Descovich, Martina; Horvai, Andrew E.; Clapp, D. Wade; Nakamura, Jean L.; Radiation Oncology, School of MedicineBackground: Genetically susceptible individuals can develop malignancies after irradiation of normal tissues. In the context of therapeutic irradiation, it is not known whether irradiating benign neoplasms in susceptible individuals promotes neoplastic transformation and worse clinical outcomes. Individuals with Neurofibromatosis 1 (NF1) are susceptible to both radiation-induced second malignancies and spontaneous progression of plexiform neurofibromas (PNs) to malignant peripheral nerve sheath tumors (MPNSTs). The role of radiotherapy in the treatment of benign neoplasms such as PNs is unclear. Methods: To test whether radiotherapy promotes neoplastic progression of PNs and reduces overall survival, we administered spinal irradiation (SI) to conditional knockout mouse models of NF1-associated PNs in 2 germline contexts: Nf1 fllfl ; PostnCre + and Nf1 fl/- ; PostnCre + . Both genotypes develop extensive Nf1 null spinal PNs, modeling PNs in NF1 patients. A total of 101 mice were randomized to 0 Gy, 15 Gy (3 Gy × 5), or 30 Gy (3 Gy × 10) of spine-focused, fractionated SI and aged until signs of illness. Results: SI decreased survival in both Nf1 fllfl mice and Nf1 fl/- mice, with the worst overall survival occurring in Nf1 fl/- mice receiving 30 Gy. SI was also associated with increasing worrisome histologic features along the PN-MPNST continuum in PNs irradiated to higher radiation doses. Conclusions: This preclinical study provides experimental evidence that irradiation of pre-existing PNs reduces survival and may shift PNs to higher grade neoplasms.Item Monitoring the Effects of Anti-angiogenesis on the Radiation Sensitivity of Pancreatic Cancer Xenografts Using Dynamic Contrast-Enhanced CT(Elsevier, 2014-02-01) Cao, Ning; Cao, Minsong; Chin-Sinex, Helen; Mendonca, Marc; Ko, Song-Chu; Stantz, Keith M; Department of Radiation Oncology, IU School of MedicinePurpose To image the intra-tumor vascular physiological status of pancreatic tumors xenografts and their response to anti-angiogenic therapy using Dynamic Contrast-Enhanced CT (DCE-CT), and to identify parameters of vascular physiology associated with tumor X-ray sensitivity following anti-angiogenic therapy. Methods and Materials Nude mice bearing human BxPC-3 pancreatic tumor xenografts were treated with 5Gy of radiation therapy (RT), either a low-dose (40mg/kg) or a high-dose (150mg/kg) of DC101, the anti-VEGF receptor-2 anti-angiogenesis antibody, or with combination of low or high dose DC101 and 5Gy RT (DC101-plus-RT). DCE-CT scans were longitudinally acquired over three week period post-DC101 treatment. Parametric maps of tumor perfusion and fractional plasma volume (Fp) were calculated and their averaged values and histogram distributions evaluated and compared to controls, from which a more homogeneous physiological window was observed 1-week post-DC101. Mice receiving a combination of DC101-plus-RT(5Gy) were imaged baseline prior to receiving DC101 and 1-week after DC101 (prior to RT). Changes in perfusion and Fp were compared with alternation in tumor growth delay for RT and DC101-plus-RT(5Gy) treated tumors. Results Pretreatment with low or high doses of DC101 prior to RT significantly delayed tumor growth by an average 7.9 days compared to RT alone (p≤0.01). The increase in tumor growth delay for the DC101-plus-RT treated tumors was strongly associated with changes in tumor perfusion (ΔP>−15%) compared to RT treated tumors alone (p=0.01). In addition, further analysis revealed a trend linking the tumor’s increased growth delay to its tumor volume-to-DC101 dose ratio. Conclusions DCE-CT is capable of monitoring changes in intra-tumor physiological parameter of tumor perfusion in response to anti-angiogenic therapy of a pancreatic human tumor xenograft that was associated with enhanced radiation response.Item Radiation therapy generates platelet-activating factor agonists(Impact Journals, 2016-04-12) Sahu, Ravi P.; Harrison, Kathleen A.; Weyerbacher, Jonathan; Murphy, Robert C.; Konger, Raymond L.; Garrett, Joy Elizabeth; Chin-Sinex, Helen Jan; Johnston II., Michael Edward; Dynlacht, Joseph R.; Mendonca, Marc; McMullen, Kevin; Li, Gengxin; Spandau, Dan F.; Travers, Jeffrey B.; Department of Dermatology, IU School of MedicinePro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens.Item Specific Functions of the Tumor Suppressor P53 are Activated by P73 and VHL(2019-07) Wolf, Eric R.; Mayo, Lindsey; Goebl, Mark; Ivan, Mircea; Mendonca, Marc; Wells, ClarkThe transcription factor and tumor suppressor protein p53 critically regulates cell survival or death in response to cellular stress. p53 can activate genes involved in a wide variety of processes, including apoptosis, cell cycle arrest, angiogenesis, metabolism, and senescence. Mutations in p53 are common in cancer and alter its interactions with other proteins, but there are other mechanisms and posttranslational modifications that can alter these interactions as well. In some tumors, such as renal cell carcinoma, p53 is commonly inactive even though mutations to TP53 are rare. This suggests that there are other biochemical mechanisms of inhibition, which we explore in this study. Mutations in the DNA-binding domain of p53 result in conformational changes that enable p53 to interact with and inhibit its family member p73, thereby promoting cell survival instead of apoptosis. In contrast, it has been reported that wild-type p53 does not bind to p73. We found that JNK-mediated phosphorylation of Thr81 in the proline-rich domain (PRD) of p53 enabled wild-type p53 to form a complex with p73. The dimerization of wild-type p53 with p73 facilitated the expression of apoptotic target genes such as PUMA and BAX, as well as the induction of apoptosis. In addition to the apoptotic function of p53, the tumor suppressor also plays a major role in the inhibition of angiogenesis. Here we also report a new mechanism where the Mdm2 oncoprotein can indirectly inactive p53 through the regulation of the tumor suppressor VHL. In response to hypoxia, VHL can bind p53, which results in activation of several anti-angiogenic targets of p53 such as THBS1 and COL18A1. Mdm2 regulates the VHL-p53 interaction by conjugating nedd8 to VHL within a region that is important for the VHL-p53 interaction, blocking the induction of anti-angiogenic genes and resulting in a proangiogenic phenotype. Due to its positive regulation of major proangiogenic proteins and its negative regulation of potent inhibitors of angiogenesis, we propose that the oncoprotein Mdm2 is the angiogenic switch. These findings refine our understanding of p53 interactions and activation, specifically for p53-p73 induced cell death and p53-VHL inhibition of angiogenesis.Item Workshop Report for Cancer Research: Defining the Shades of Gy: Utilizing the Biological Consequences of Radiotherapy in the Development of New Treatment Approaches—Meeting Viewpoint(AACR, 2018-05) Ahmed, Mansoor M.; Coleman, C. Norman; Mendonca, Marc; Bentzen, Soren; Vikram, Bhadrasain; Seltzer, Stephen M.; Goodhead, Dudley; Obcemea, Ceferino; Mohan, Radhe; Prise, Kevin M.; Capala, Jacek; Citrin, Deborah; Kao, Gary; Aryankalayil, Molykutty; Eke, Iris; Buchsbaum, Jeffrey C.; Prasanna, Pataje G. S.; Liu, Fei-Fei; Le, Quynh-Thu; Teicher, Beverly; Kirsch, David G.; Smart, DeeDee; Tepper, Joel; Formenti, Silvia; Haas-Kogan, Daphne; Raben, David; Mitchell, James; Radiation Oncology, School of MedicineThe ability to physically target radiotherapy using image-guidance is continually improving with photons and particle therapy that include protons and heavier ions such as carbon. The unit of dose deposited is the gray (Gy); however, particle therapies produce different patterns of ionizations, and there is evidence that the biological effects of radiation depend on dose size, schedule, and type of radiation. This National Cancer Institute (NCI)–sponsored workshop addressed the potential of using radiation-induced biological perturbations in addition to physical dose, Gy, as a transformational approach to quantifying radiation.