D Dr ru ug g--r re es si is st ta an nt t t tu ub be er rc cu ul lo os si is s i in n tABSTRACT: There has been an upsurge of tuberculosis in many parts of the world in the past decade. The high rates of drug-resistant tuberculosis currently reported in many countries are alarming. The most catastrophic phenomenon is the emergence of multidrug-resistant strains of Mycobacterium tuberculosis. These organisms have caused epidemic outbreaks in nosocomial and health-care settings in the USA and some European countries. In addition to immigration, poverty, alcoholism and intravenous substance abuse, human immunodeficiency virus (HIV) infection has also had a significant impact on the prevalence of drug resistance, since amongst these patient groups a common factor giving rise to drug resistance is noncompliance.Rapid drug susceptibility tests are needed, and effective chemotherapy regimens with newly developed drugs in combination with traditional second-line antituberculosis agents for established multidrug-resistant tuberculosis are urgently being sought. There is also a quest for other novel modalities of therapy. Measures should be actively adopted to prevent the development of drug resistance. Well formulated short-course chemotherapy as initial treatment and ensurance of compliance are the most important components. The organization of a national tuberculosis control programme with a sound and adequately functioning infrastructure remains the most effective strategy to combat the resurgence of tuberculosis and to curtail drug resistance.
Elements of the hypoxia inducible factor (HIF) transcriptional system, a key regulator of the cellular hypoxic response, are up-regulated in a range of cancer cells. HIF is fundamentally involved in tumor angiogenesis, invasion, and energy metabolism. Inhibition of the transcriptional activity of HIF may be of therapeutic benefit to cancer patients. We recently described the identification of two marine pyrroloiminoquinone alkaloids with potent activity in inhibiting the interaction between the oncogenic transcription factor HIF-1α and the coactivator protein p300. Herein, we present further characterization data for these two screening hits: discorhabdin H (1) and discorhabdin L (2), with a specific focus on their anti-angiogenic and anti-tumor effects. We demonstrated that only discorhabdin L (2) possesses excellent anti-angiogenic activity in inhibiting endothelial cell proliferation and tube formation, as well as decreasing microvessel outgrowth in the ex vivo rat aortic ring assay. We further showed that discorhabdin L (2) significantly inhibits in vivo prostate tumor growth in a LNCaP xenograft model. In conclusion, our findings suggest that discorhabdin L (2) represents a promising HIF-1α inhibitor worthy of further drug development.
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