HIF-1 is associated with poor prognoses and therapeutic resistance in cancer patients. We previously developed a novel hypoxia-inducible factor (HIF)-1 inhibitor, IDF-11774, a clinical candidate for cancer therapy. We also reported that IDF-1174 inhibited HSP70 chaperone activity and suppressed accumulation of HIF-1α. In this study, IDF-11774 inhibited the accumulation of HIF-1α in vitro and in vivo in colorectal carcinoma HCT116 cells under hypoxic conditions. Moreover, IDF-11774 treatment suppressed angiogenesis of cancer cells by reducing the expression of HIF-1 target genes, reduced glucose uptake, thereby sensitizing cells to growth under low glucose conditions, and decreased the extracellular acidification rate (ECAR) and oxygen consumption rate of cancer cells. Metabolic profiling of IDF-11774-treated cells revealed low levels of NAD+, NADP+, and lactate, as well as of intermediates in glycolysis and the tricarboxylic acid cycle. In addition, we observed elevated AMP and diminished ATP levels, resulting in a high AMP/ATP ratio. The level of AMP-activated protein kinase phosphorylation also increased, leading to inhibition of mTOR signaling in treated cells. In vivo xenograft assays demonstrated that IDF-11774 exhibited substantial anticancer efficacy in mouse models containing KRAS, PTEN, or VHL mutations, which often occur in malignant cancers. Collectively, our data indicate that IDF-11774 suppressed hypoxia-induced HIF-1α accumulation and repressed tumor growth by targeting energy production-related cancer metabolism.

A new series of geldanamycin derivatives were synthesized using a semi-synthetic approach involving genetically engineered biosynthetic intermediates. These analogues were then evaluated for anti-proliferation activity in human cancer cell lines, SK-Br3 and SK-Ov3. Most of the synthesized compounds exhibited potent in vitro anti-proliferation activity toward both cell lines. Such compounds potently inhibited the expression of the Hsp90 client protein ErbB2.

BackgroundThe IDF-11774, a novel clinical candidate for cancer therapy, targets HSP70 and inhibits mitochondrial respiration, resulting in the activation of AMPK and reduction in HIF-1α accumulation.MethodsTo identify genes that have synthetic lethality to IDF-11774, RNA interference screening was conducted, using pooled lentiviruses expressing a short hairpin RNA library.ResultsWe identified ATP6V0C, encoding the V0 subunit C of lysosomal V-ATPase, knockdown of which induced a synergistic growth-inhibitory effect in HCT116 cells in the presence of IDF-11774. The synthetic lethality of IDF-11774 with ATP6V0C possibly correlates with IDF-11774-mediated autolysosome formation. Notably, the synergistic effect of IDF-11774 and the ATP6V0C inhibitor, bafilomycin A1, depended on the PIK3CA genetic status and Bcl-2 expression, which regulates autolysosome formation and apoptosis. Similarly, in an experiment using conditionally reprogramed cells derived from colorectal cancer patients, synergistic growth inhibition was observed in cells with low Bcl-2 expression.ConclusionsBcl-2 is a biomarker for the synthetic lethal interaction of IDF-11774 with ATP6V0C, which is clinically applicable for the treatment of cancer patients with IDF-11774 or autophagy-inducing anti-cancer drugs.

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Owing to increasing concern regarding human well-being and quality of life, the demand for natural products is increased, leading to the development of a market for biological and natural products. This study aimed to investigate the depigmentation and anti-ageing properties of red seaweed (Pyropia yezoensis) extracts for skin care applications. Within the tested range of concentrations (100, 200, 400, and 800 μg mL −1 ), P. yezoensis extracts did not exert cytotoxic effects on the three skin cell lines tested: mouse melanocytes (Melan-A), human dermal fibroblasts (1064 SK), and human dermal keratinocytes (HaCaT cells). No significant statistical difference (p = 0.05) was detected in the melanin content between cells exposed to 100 μg mL −1 of arbutin and 800 μg mL −1 of P. yezoensis extracts, indicating that P. yezoensis extracts had an potent inhibitory effect on melanogenesis as arbutin. There was a significant decrease in tyrosinase activity by 59.3% and 35.5% after treatment with arbutin and P. yezoensis extracts, respectively. These results indicated that P. yezoensis extracts had strong tyrosinase inhibitory properties but were not as effective as arbutin. P. yezoensis extracts also promoted collagen production by inhibiting collagen-degrading enzymes (matrix metalloproteinase (MMP)-2 and MMP-9) and promoting procollagen synthesis enzymes (tyrosinase-related protein (TRP)-1 and TRP-2). Evaluation of skin brightness and melanin content and dermatological assessment showed that P. yezoensis extracts enhanced skin brightness and reduced melanin content in 23 volunteers. Our results suggest that P. yezoensis extracts can be used as functional cosmetic agents to prevent, or remediate skin ageing and pigmentation.