Leptin stimulates migration and invasion and maintains cancer stem­like properties in gastric cancer cells.

Obesity is a risk factor for various types of cancer. Leptin, an adipocyte­derived hormone, may stimulate the proliferation of gastric cancer cells. However, the effect of leptin and underlying mechanism in gastric cancer remain unclear. In the present study, the role of leptin in gastric cancer was evaluated. The effect of leptin on the JAK­STAT and MEK signaling pathways was investigated in gastric cancer cells using wound­healing and cell invasion assays, immunoblotting and inhibition studies. Cancer­initiating cells derived from gastric cancer cells were used to investigate the effect of leptin on the maintenance of stemness and epithelial­mesenchymal transition (EMT) by immunoblotting. Clinicopathological characteristics including the serum leptin level and overall survival (OS) were analyzed in patients with (n=23) and without (n=23) obesity. Leptin induced the migration and invasion of gastric cancer cells by activating AKT and ERK and upregulating vascular endothelial growth factor (VEGF). Leptin increased the mRNA and protein levels of markers of stemness (CD44) and the EMT (Snail and N­cadherin). Pharmacological inhibitors of the JAK­STAT and MEK signaling pathways decreased leptin­induced migration and invasion, and the expression of VEGF. Obesity was associated with an elevated leptin level and body mass index was positively correlated with the leptin level (P=0.001 for both). The 5­year OS rate was not significantly different between the two groups (P=0.098). Leptin stimulates the migration and invasion of gastric cancer cells by activating the JAK­STAT and MEK pathways, and contributes to the maintenance of cancer stemness and metastatic potential. The present findings support an adverse effect of obesity in gastric cancer. Consequently, targeting of leptin­associated signaling pathways may have therapeutic potential for gastric cancer.

Radotinib Induces Apoptosis of CD11b+ Cells Differentiated from Acute Myeloid Leukemia Cells.

Radotinib, developed as a BCR/ABL tyrosine kinase inhibitor (TKI), is approved for the second-line treatment of chronic myeloid leukemia (CML) in South Korea. However, therapeutic effects of radotinib in acute myeloid leukemia (AML) are unknown. In the present study, we demonstrate that radotinib significantly decreases the viability of AML cells in a dose-dependent manner. Kasumi-1 cells were more sensitive to radotinib than NB4, HL60, or THP-1 cell lines. Furthermore, radotinib induced CD11b expression in NB4, THP-1, and Kasumi-1 cells either in presence or absence of all trans-retinoic acid (ATRA). We found that radotinib promoted differentiation and induced CD11b expression in AML cells by downregulating LYN. However, CD11b expression induced by ATRA in HL60 cells was decreased by radotinib through upregulation of LYN. Furthermore, radotinib mainly induced apoptosis of CD11b+ cells in the total population of AML cells. Radotinib also increased apoptosis of CD11b+ HL60 cells when they were differentiated by ATRA/dasatinib treatment. We show that radotinib induced apoptosis via caspase-3 activation and the loss of mitochondrial membrane potential (ΔΨm) in CD11b+ cells differentiated from AML cells. Our results suggest that radotinib may be used as a candidate drug in AML or a chemosensitizer for treatment of AML by other therapeutics.

Rosmarinic acid potentiates ATRA-induced macrophage differentiation in acute promyelocytic leukemia NB4 cells.

Rosmarinic acid (RA, an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid) has a number of biological activities, but little is known about anti-leukemic activities of RA combined with all-trans retinoic acid (ATRA) against acute promyelocytic leukemia (APL) cells. We examined the differentiation marker, CD11b, in bone marrow cells (BMC) of an APL patient, in NB4 cells (APL cell line), and in normal BMC and peripheral blood mononuclear cells (PBMC) of healthy subjects by flow cytometric analysis. ATRA/RA induced expression of CD11b in the BMC of the APL patient and in NB4 cells, but not in normal BMC or PBMC. Therefore, we realized that RA potentiated ATRA-induced macrophage differentiation in APL cells. Further characterization of the induced macrophages showed that they exhibited morphological changes and were able to phagocytose and generate reactive oxygen species. Th also had typical expression of C-C chemokine receptor type 1 (CCR1), CCR2, and intercellular adhesion molecule-1 (ICAM-1). Moreover, the expression of CD11b(+) and CD14(+) cells depended on ERK-NF-κB axis activation. Together, these results indicate that RA potentiates ATRA-induced macrophage differentiation in APL cells. Thus, RA may play an important role as an appurtenant differentiation agent for functional macrophage differentiation in APL. Additionally, the differentiated macrophages might have a normal life span and, they could die. These data indicate that co-treatment with RA and ATRA has potential as an anti-leukemic therapy in APL.

Capsaicin suppresses the migration of cholangiocarcinoma cells by down-regulating matrix metalloproteinase-9 expression via the AMPK-NF-κB signaling pathway.

Cholangiocarcinoma is one of the most difficult malignancies to cure. An important prognostic factor is metastasis, which precludes curative surgical resection. Recent evidence shows that capsaicin has an inhibitory effect on cancer cell migration and invasion. Here, we investigated the molecular mechanism of the capsaicin-induced anti-migration and anti-invasion effects on HuCCT1 cholangiocarcinoma cells. Migration and invasion were significantly reduced in response to capsaicin. Capsaicin also inhibited the expression of matrix metalloproteinase-9 (MMP-9). In capsaicin-treated cells, levels of phosphorylated AMPK increased, and this effect was abolished by treatment with the AMPK inhibitor, Compound C. Capsaicin enhanced the expression of SIRT1, which can activate the transcription factor NF-κB by deacetylation. This suggests that NF-κB is activated by capsaicin via the SIRT1 pathway. In addition, capsaicin-activated AMPK induced the phosphorylation of IκBα and nuclear localization of NF-κB p65. Chromatin immunoprecipitation assays demonstrated that capsaicin reduced MMP-9 transcription by inhibiting NF-κB p65 translocation and deacetylation via SIRT1. These findings provide evidence that capsaicin suppresses the migration and invasion of cholangiocarcinoma cells by inhibiting NF-κB p65 via the AMPK-SIRT1 and the AMPK-IκBα signaling pathways, leading to subsequent suppression of MMP-9 expression.

Dasatinib accelerates valproic acid-induced acute myeloid leukemia cell death by regulation of differentiation capacity.

Dasatinib is a compound developed for chronic myeloid leukemia as a multi-targeted kinase inhibitor against wild-type BCR-ABL and SRC family kinases. Valproic acid (VPA) is an anti-epileptic drug that also acts as a class I histone deacetylase inhibitor. The aim of this research was to determine the anti-leukemic effects of dasatinib and VPA in combination and to identify their mechanism of action in acute myeloid leukemia (AML) cells. Dasatinib was found to exert potent synergistic inhibitory effects on VPA-treated AML cells in association with G1 phase cell cycle arrest and apoptosis induction involving the cleavage of poly (ADP-ribose) polymerase and caspase-3, -7 and -9. Dasatinib/VPA-induced cell death thus occurred via caspase-dependent apoptosis. Moreover, MEK/ERK and p38 MAPK inhibitors efficiently inhibited dasatinib/VPA-induced apoptosis. The combined effect of dasatinib and VPA on the differentiation capacity of AML cells was more powerful than the effect of each drug alone, being sufficiently strong to promote AML cell death through G1 cell cycle arrest and caspase-dependent apoptosis. MEK/ERK and p38 MAPK were found to control dasatinib/VPA-induced apoptosis as upstream regulators, and co-treatment with dasatinib and VPA to contribute to AML cell death through the regulation of differentiation capacity. Taken together, these results indicate that combined dasatinib and VPA treatment has a potential role in anti-leukemic therapy.

Topical application of capsaicin reduces visceral adipose fat by affecting adipokine levels in high-fat diet-induced obese mice.

OBJECTIVE: Visceral obesity contributes to the development of obesity-related disorders such as diabetes, hyperlipidemia, and fatty liver disease, as well as cardiovascular diseases. In this study, we determined whether topical application of capsaicin can reduce fat accumulation in visceral adipose tissues. METHODS AND RESULTS: We first observed that topical application of 0.075% capsaicin to male mice fed a high-fat diet significantly reduced weight gain and visceral fat. Fat cells were markedly smaller in the mesenteric and epididymal adipose tissues of mice treated with capsaicin cream. The capsaicin treatment also lowered serum levels of fasting glucose, total cholesterol, and triglycerides. Immunoblot analysis and RT-PCR revealed increased expression of adiponectin and other adipokines including peroxisome proliferator-activated receptor (PPAR) α, PPARγ, visfatin, and adipsin, but reduced expression of tumor necrosis factor-α and IL-6. CONCLUSIONS: These results indicate that topical application of capsaicin to obese mice limits fat accumulation in adipose tissues and may reduce inflammation and increase insulin sensitivity.