RESUMO
Human polynucleotide phosphorylase (hPNPase(old-35)) is an evolutionary conserved RNA-processing enzyme with expanding roles in regulating cellular physiology. hPNPase(old-35) was cloned using an innovative 'overlapping pathway screening' strategy designed to identify genes coordinately regulated during the processes of cellular differentiation and senescence. Although hPNPase(old-35) structurally and biochemically resembles PNPase of other species, overexpression and inhibition studies reveal that hPNPase(old-35) has evolved to serve more specialized and diversified functions in humans. Targeting specific mRNA or non-coding small microRNA, hPNPase(old-35) modulates gene expression that in turn has a pivotal role in regulating normal physiological and pathological processes. In these contexts, targeted overexpression of hPNPase(old-35) represents a novel strategy to selectively downregulate RNA expression and consequently intervene in a variety of pathophysiological conditions.
Assuntos
Sequência Conservada , Evolução Molecular , Polirribonucleotídeo Nucleotidiltransferase/genética , RNA/metabolismo , Humanos , HidróliseRESUMO
Polysaccharides such as glucans are the best known and most potent mushroom-derived substances with antitumor and immunomodulating properties. However, a vast variety of mushroom species remain unexplored. The present study aims at exploring the possible role of a heteroglucan designated as AE2, isolated from Astraeus hygrometricus, on tumor bearing host. AE2 mediated tumor regression through the reversal of tumor induced immunosupression. Tumor-associated macrophages from AE2 administered tumor bearing host have been demonstrated to possess augmented surface expression of co-stimulatory molecules and MHC-II, representing essentially elevated state of macrophage activation. NK cell activity has also been found to be elevated with the AE2 treatment while the Th1 cytokine in the tumor micro-environment increases with the treatment, the Th2 cytokine levels concomitantly decreases. Further, following the immunoactivation, Daltons lymphoma (DL) cells has undergone apoptosis, thereby resulting in reduction of tumor growth and increased survival rate of the tumor bearing host. The present study sheds light on the potent antitumor property of the heteroglucan AE2 isolated from A. hygrometricus, and can be extended further to develop therapeutic protocols for treatment of cancer or disease resulting in immunosuppression.
Assuntos
Agaricales/química , Antineoplásicos/farmacologia , Glucanos/farmacologia , Linfoma/tratamento farmacológico , Animais , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Corantes , Carpóforos/química , Glucanos/isolamento & purificação , Células Matadoras Naturais/efeitos dos fármacos , Linfoma/patologia , Macrófagos/efeitos dos fármacos , Manose/metabolismo , Camundongos , Transplante de Neoplasias , Nitritos/metabolismo , Fagocitose/efeitos dos fármacos , Polissacarídeos/química , Análise de Sobrevida , Sais de Tetrazólio , TiazóisRESUMO
Gene therapy is being examined as a potential strategy for treating prostate cancer. Serotype 5 adenovirus (Ad.5) is routinely used as a vector for transgene delivery. However, the infectivity of Ad.5 is dependent on Coxsackie-adenovirus receptors (CARs); many tumor types show a reduction in this receptor in vivo, thereby limiting therapeutic gene transduction. Serotype chimerism is one approach to circumvent CAR deficiency; this strategy is used to generate an Ad.5/3-recombinant Ad that infects cancer cells through Ad.3 receptors in a CAR-independent manner. In this report, the enhanced transgene delivery and efficacy of Ad.5/3-recombinant virus was evaluated using an effective wide-spectrum anticancer therapeutic melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24). Our data show that in low CAR human prostate cancer cells (PC-3), a recombinant Ad.5/3 virus delivering mda-7/IL-24 (Ad.5/3-mda-7) is more efficacious than an Ad.5 virus encoding mda-7/IL-24 (Ad.5-mda-7) in infecting tumor cells, expressing MDA-7/IL-24 protein, inducing cancer-specific apoptosis, inhibiting in vivo tumor growth and exerting an antitumor 'bystander' effect in a nude mouse xenograft model. Considering the fact that Ad.5-mda-7 has shown significant objective responses in a phase I clinical trial for solid tumors, Ad.5/3-mda-7 is predicted to exert enhanced therapeutic benefit in patients with prostate cancer.
