MnTE-2-PyP and Radiation in a Prostate Cancer Model: Implications for Radiotherapy

A major limitation of successful radiation therapy in cancer treatment is the increase in normal tissue damage as higher doses are used to achieve greater tumor destruction. Radiation dose optimization in cancer therapy requires achieving maximum tumor destruction with minimal damage to normal tissue Antioxidants have been shown to protect normal tissues against radiation damage, as radiation-induced tissue damage results predominantly from reactive oxygen species that directly damage cellular components. However, for effective use as normal tissue radioprotectants in radiotherapy, these antioxidants must not protect the tumors. Mn (III) tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP) is a metalloporphyrin antioxidant that has been shown to have radioprotective properties in normal tissue. The major objective of this project was to evaluate the effects of MnTE-2-PyP on prostate cancer response to radiation and to explore mechanisms responsible for the observed effects. Our results showed that radiation significantly slowed tumor progression and addition of MnTE-2-PyP does not significantly alter tumor growth. However, the evaluation of cytokines in spleen, plasma and tumors suggest that administration of MnTE-2-PyP together with radiotherapy may enhance anti-tumor immune responsiveness and decrease the risk for radiation-induced normal tissue toxicities. Assessment of the effects of Mn-TE-2-PyP on radiation response in human prostate cancer cell lines showed that drug did not protect PCa cells against radiation. In addition, in LNCaP cells, a dose-dependent decrease in DNA synthesis and cell viability was observed with drug treatment. The clinical relevance of this cell line makes it noteworthy, as they are a close representative of prostate cancer that would be treated with radiation therapy in patients. Overall, it was demonstrated that the MnTE-2- PyP does not protect prostate tumors against radiation damage and is not toxic under the conditions used. In addition, the drug-induced enhancement of certain immune parameters suggests that MnTE-2-PyP may be beneficial not only as a normal tissue radioprotectant, but also as a facilitator of antitumor immunity. This study enhances the clinical relevance of antioxidant metalloporphyrins and potentially contributes towards improvement of cancer treatment and radiotherapy

mRNA Expression Profiles for Prostate Cancer following Fractionated Irradiation Are Influenced by p53 Status

AbstractWe assessed changes in cell lines of varying p53 status after various fractionation regimens to determine if p53 influences gene expression and if multifractionated (MF) irradiation can induce molecular pathway changes. LNCaP (p53 wild-type), PC3 (p53 null), and DU145 (p53 mutant) prostate carcinoma cells received 5 and 10 Gy as single-dose (SD) or MF (0.5 Gy × 10, 1 Gy × 10, and 2 Gy × 5) irradiation to simulate hypofractionated and conventionally fractionated prostate radiotherapies, respectively. mRNA analysis revealed 978 LNCaP genes differentially expressed (greater than two-fold change, P < .05) after irradiation. Most were altered with SD (69%) and downregulated (75%). Fewer PC3 (343) and DU145 (116) genes were induced, with most upregulated (87%, 89%) and altered with MF irradiation. Gene ontology revealed immune response and interferon genes most prominently expressed after irradiation in PC3 and DU145. Cell cycle regulatory (P = 9.23 × 10-73, 14.2% of altered genes, nearly universally downregulated) and DNA replication/repair (P = 6.86 × 10-30) genes were most prominent in LNCaP. Stress response and proliferation genes were altered in all cell lines. p53-activated genes were only induced in LNCaP. Differences in gene expression exist between cell lines and after varying irradiation regimens that are p53 dependent. As the duration of changes is ≥24 hours, it may be possible to use radiation-inducible targeted therapy to enhance the efficacy of molecular targeted agents

Exploring the Influence of Daily Climate Variables on Malaria Transmission and Abundance of Anopheles arabiensis over Nkomazi Local Municipality, Mpumalanga Province, South Africa

The recent resurgence of malaria incidence across epidemic regions in South Africa has been linked to climatic and environmental factors. An in-depth investigation of the impact of climate variability and mosquito abundance on malaria parasite incidence may therefore offer useful insight towards the control of this life-threatening disease. In this study, we investigate the influence of climatic factors on malaria transmission over Nkomazi Municipality. The variability and interconnectedness between the variables were analyzed using wavelet coherence analysis. Time-series analyses revealed that malaria cases significantly declined after the outbreak in early 2000, but with a slight increase from 2015. Furthermore, the wavelet coherence and time-lagged correlation analyses identified rainfall and abundance of Anopheles arabiensis as the major variables responsible for malaria transmission over the study region. The analysis further highlights a high malaria intensity with the variables from 1998–2002, 2004–2006, and 2010–2013 and a noticeable periodicity value of 256–512 days. Also, malaria transmission shows a time lag between one month and three months with respect to mosquito abundance and the different climatic variables. The findings from this study offer a better understanding of the importance of climatic factors on the transmission of malaria. The study further highlights the significant roles of An. arabiensis on malaria occurrence over Nkomazi. Implementing the mosquito model to predict mosquito abundance could provide more insight into malaria elimination or control in Africa

Exploring the Influence of Daily Climate Variables on Malaria Transmission and Abundance of Anopheles arabiensis over Nkomazi Local Municipality, Mpumalanga Province, South Africa.

The recent resurgence of malaria incidence across epidemic regions in South Africa has been linked to climatic and environmental factors. An in-depth investigation of the impact of climate variability and mosquito abundance on malaria parasite incidence may therefore offer useful insight towards the control of this life-threatening disease. In this study, we investigate the influence of climatic factors on malaria transmission over Nkomazi Municipality. The variability and interconnectedness between the variables were analyzed using wavelet coherence analysis. Time-series analyses revealed that malaria cases significantly declined after the outbreak in early 2000, but with a slight increase from 2015. Furthermore, the wavelet coherence and time-lagged correlation analyses identified rainfall and abundance of Anopheles arabiensis as the major variables responsible for malaria transmission over the study region. The analysis further highlights a high malaria intensity with the variables from 1998-2002, 2004-2006, and 2010-2013 and a noticeable periodicity value of 256-512 days. Also, malaria transmission shows a time lag between one month and three months with respect to mosquito abundance and the different climatic variables. The findings from this study offer a better understanding of the importance of climatic factors on the transmission of malaria. The study further highlights the significant roles of An. arabiensis on malaria occurrence over Nkomazi. Implementing the mosquito model to predict mosquito abundance could provide more insight into malaria elimination or control in Africa