BackgroundPhosphoinositide 3-kinase (PI3K)/Akt pathway is linked to the development of asthma. Anti-malarial drug artesunate is a semi-synthetic derivative of artemisinin, the principal active component of a medicinal plant Artemisia annua, and has been shown to inhibit PI3K/Akt activity. We hypothesized that artesunate may attenuate allergic asthma via inhibition of the PI3K/Akt signaling pathway.Methodology/Principal FindingsFemale BALB/c mice sensitized and challenged with ovalbumin (OVA) developed airway inflammation. Bronchoalveolar lavage fluid was assessed for total and differential cell counts, and cytokine and chemokine levels. Lung tissues were examined for cell infiltration and mucus hypersecretion, and the expression of inflammatory biomarkers. Airway hyperresponsiveness was monitored by direct airway resistance analysis. Artesunate dose-dependently inhibited OVA-induced increases in total and eosinophil counts, IL-4, IL-5, IL-13 and eotaxin levels in bronchoalveolar lavage fluid. It attenuated OVA-induced lung tissue eosinophilia and airway mucus production, mRNA expression of E-selectin, IL-17, IL-33 and Muc5ac in lung tissues, and airway hyperresponsiveness to methacholine. In normal human bronchial epithelial cells, artesunate blocked epidermal growth factor-induced phosphorylation of Akt and its downstream substrates tuberin, p70S6 kinase and 4E-binding protein 1, and transactivation of NF-κB. Similarly, artesunate blocked the phosphorylation of Akt and its downstream substrates in lung tissues from OVA-challenged mice. Anti-inflammatory effect of artesunate was further confirmed in a house dust mite mouse asthma model.Conclusion/SignificanceArtesunate ameliorates experimental allergic airway inflammation probably via negative regulation of PI3K/Akt pathway and the downstream NF-κB activity. These findings provide a novel therapeutic value for artesunate in the treatment of allergic asthma.

NCT01184807.

The ability to selectively eradicate oncogene-addicted tumors while reducing systemic toxicity has endeared targeted therapies as a treatment strategy. Nevertheless, development of acquired resistance limits the benefits and durability of such a regime. Here we report evidence of enhanced reliance on mitochondrial oxidative phosphorylation (OXPHOS) in oncogene-addicted cancers manifesting acquired resistance to targeted therapies. To that effect, we describe a novel OXPHOS targeting activity of the small molecule compound, OPB-51602 (OPB). Of note, a priori treatment with OPB restored sensitivity to targeted therapies. Furthermore, cancer cells exhibiting stemness markers also showed selective reliance on OXPHOS and enhanced sensitivity to OPB. Importantly, in a subset of patients who developed secondary resistance to EGFR tyrosine kinase inhibitor (TKI), OPB treatment resulted in decrease in metabolic activity and reduction in tumor size. Collectively, we show here a switch to mitochondrial OXPHOS as a key driver of targeted drug resistance in oncogene-addicted cancers. This metabolic vulnerability is exploited by a novel OXPHOS inhibitor, which also shows promise in the clinical setting.

Genomic analyses of squamous cell carcinoma (SCC) have yet to yield significant strategies against pathway activation to improve treatment. Platinum-based chemotherapy remains the mainstay of treatment for SCC of different histotypes either as a single-agent or alongside other chemotherapeutic drugs or radiotherapy; however, resistance inevitably emerges, which limits the duration of treatment response. To elucidate mechanisms that mediate resistance to cisplatin, we compared drug-induced perturbations to gene and protein expression between cisplatinsensitive and -resistant SCC cells, and identified MAPK-ERK pathway upregulation and activation in drug-resistant cells.