Metformin is a biguanide widely prescribed as an antidiabetic drug for type 2 diabetes mellitus patients. The purpose of the present study was to observe the effects of the new metformin derivative, HL156A, on human oral cancer cell and to investigate its possible mechanisms. It was observed that HL156A significantly decreased FaDu and YD‐10B cell viability and colony formation in a dose‐dependent way. HL156A also markedly reduced wound closure and migration of FaDu and YD‐10B cells. We observed that HL156A decreased mitochondrial membrane potential and induced reactive oxygen species (ROS) levels and apoptotic cells with caspase‐3 and ‐9 activation. HL156A inhibited the expression and activation of insulin‐like growth factor (IGF)‐1 and its downstream proteins, AKT, mammalian target of rapamycin (mTOR), and ERK1/2. In addition, HL156A activated AMP‐activated protein kinase/nuclear factor kappa B (AMPK‐NF‐κB) signaling of FaDu and YD‐10B cells. A xenograft mouse model further showed that HL156A suppressed AT84 mouse oral tumor growth, accompanied by down‐regulated p‐IGF‐1, p‐mTOR, proliferating cell nuclear antigen (PCNA) and promoted p‐AMPK and TUNEL expression. These results suggest the potential value of the new metformin derivative HL156A as a candidate for a therapeutic modality for the treatment of oral cancer.

The highly heterogenous nature of colorectal cancer can significantly hinder its early and accurate diagnosis, eventually contributing to high mortality rates. The adenoma-carcinoma sequence and serrated polyp-carcinoma sequence are the two most common sequences in sporadic colorectal cancer. Genetic alterations in adenomatous polyposis coli (APC), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and tumour protein 53 (TP53) genes are critical in adenoma-carcinoma sequence, whereas v-Raf murine sarcoma viral oncogene homolog B (BRAF) and MutL Homolog1 (MLH1) are driving oncogenes in the serrated polyp-carcinoma sequence. Sporadic mutations in these genes contribute differently to colorectal cancer pathogenesis by introducing distinct alterations in several signalling pathways that rely on the endosome-lysosome system. Unsurprisingly, the endosome-lysosome system plays a pivotal role in the hallmarks of cancer and contributes to specialised colon function. Thus, the endosome-lysosome system might be distinctively influenced by different mutations and these alterations may contribute to the heterogenous nature of sporadic colorectal cancer. This review highlights potential connections between major sporadic colorectal cancer mutations and the diverse pathogenic mechanisms driven by the endosome-lysosome system in colorectal carcinogenesis.

Aging is characterized by a reduced ability to defend against stress, an inability to maintain homeostasis, and an increased risk of disease. In this study, a metabolomics approach was used to identify novel metabolic pathways that are perturbed in a mouse model of accelerated aging (SAMP1/kl-/-) and to gain new insights into the metabolic associations of the metformin derivative HL156A. Extensive inflammation and calcification were observed in the tissues of the SAMP1/kl-/- mice with premature aging. In mouse embryonic fibroblasts (MEFs) obtained from SAMP1/kl-/- mice, we observed that HL156A induced FOXO1 expression through inhibition of the IGF-1/AKT/mTOR signaling pathways. Treatment of HL156A decreased reactive oxygen species production and enhanced mitochondria! transmembrane potential in SAMP1/kl-/- MEFs. A metabolomic profile analysis showed that HL156A increased the GSH/GSSG ratio in the kidneys of SAMP1/kl-/- mice (8-12 weeks old). In addition, treating SAMP1/kl-/- mice with HL156A (30 mg/kg) for 4 weeks improved survival and decreased the significant elevation of oxidized GSH (GSSG) that was observed in SAMP1/kl-/- mice. In histological sections, HL156A administered SAMP1/kl-/- mice exhibited a decrease in excessive calcification. Based on these findings, we conclude that the new metformin derivative HL156A may inhibit oxidative damage by inducing glutathione metabolism and antioxidant pathways.

Multidrug resistance is a significant clinical crisis in cancer treatment and has been linked to the cellular expression of multidrug efflux transporters. The aim of this study was to examine the effects and mechanisms of the metformin derivative HL156A on human multidrug resistance (MDR) cancer cells. Here, HL156A significantly suppressed cell growth and colony formation through G2/M phase cell cycle arrest in MDR cancer cells. HL156A also reduced the wound closure rate and cell migration and induced caspase-3-dependent apoptosis. We found that HL156A inhibited the expression of MDR1 by inhibiting the HOXC6-mediated ERK1/2 signaling pathway and increased the sensitivity to paclitaxel or doxorubicin in MDR cells. Furthermore, HL156A significantly inhibited angiogenesis in a chicken chorioallantoic membrane (CAM) assay. These results suggest the potential of the metformin derivative HL156A as a candidate therapeutic modality for the treatment of human multidrug-resistant cancers.

Background: This study focuses on the role of lysosomal trafficking in prostate cancer, given the essential role of lysosomes in cellular homoeostasis. Methods: Lysosomal motility was evaluated using confocal laser scanning microscopy of LAMP-1-transfected prostate cells and spot-tracking analysis. Expression of lysosomal trafficking machinery was evaluated in patient cohort databases and through immunohistochemistry on tumour samples. The roles of vesicular trafficking machinery were evaluated through over-expression and siRNA. The effects of R1881 treatment on lysosome vesicular trafficking was evaluated by RNA sequencing, protein quantification and fixed- and live-cell microscopy. Results: Altered regulation of lysosomal trafficking genes/proteins was observed in prostate cancer tissue, with significant correlations for co-expression of vesicular trafficking machinery in Gleason patterns. The expression of trafficking machinery was associated with poorer patient outcomes. R1881 treatment induced changes in lysosomal distribution, number, and expression of lysosomal vesicular trafficking machinery in hormone-sensitive prostate cancer cells. Manipulation of genes involved in lysosomal trafficking events induced changes in lysosome positioning and cell phenotype, as well as differential effects on cell migration, in non-malignant and prostate cancer cells. Conclusions: These findings provide novel insights into the altered regulation and functional impact of lysosomal vesicular trafficking in prostate cancer pathogenesis.