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It has been reported that [3-(1,1'-biphenyl-4-yl)-2-(1-methyl-5-dimethylamino-pentylamino)-3,4-dihydroquinazolin-4-yl]-N-benzylacetamide 2hydrochloride (KYS05090), a selective T-type Ca2+ channel blocker, reduces tumor volume and weight in the A549 xenograft model, but the molecular mechanism of cell death has not yet been elucidated. In this study, KYS05090 induced autophagy- and apoptosis-mediated cell death in human lung adenocarcinoma A549 cells. Although KYS05090 decreased intracellular Ca2+ levels, it was not directly related with KYS05090-induced cell death. In addition, KYS05090 generated intracellular reactive oxygen species (ROS) and reduced glucose uptake, and catalase and methyl pyruvate prevented KYS05090-induced cell death. These results indicate that KYS05090 can lead to autophagy and apoptosis in A549 cells through ROS generation by inhibiting glucose uptake. Our findings suggest that KYS05090 has potential chemotherapeutic value for the treatment of lung cancer.

Previously, we reported that 6,7-dimethoxy-3-(3-methoxyphenyl)isoquinolin-1-amine (CWJ-082) has potent cytotoxic effects on various cancer cells, but the underlying molecular mechanism responsible was not determined. In the present study, CWJ-082 caused cervical cancer cell cycle arrest at the G2/M phase and subsequent caspase-dependent apoptosis. The mitotic arrest caused by CWJ-082 found to be due to increases in the activation of cyclin-dependent kinase 1/cyclin B1 complex and the phosphorylation of histone H3. In addition, CWJ-082 induced the phosphorylation of BubR1 and the association between mitotic arrest deficient 2 (Mad2) and cell division cycle protein 20. These findings suggested that CWJ-082 activated the mitotic spindle checkpoint. Furthermore, knockdown of the spindle checkpoint proteins BubR1 or Mad2 using specific small interfering RNAs significantly reduced CWJ-082-induced mitotic cell accumulation and apoptosis. In addition, CWJ-082 induced the appearance of spindle abnormalities by inducing α-tubulin polymerization. In BALB/c(nu/nu) mice bearing a HeLa xenograft, CWJ-082 significantly inhibited tumor growth. Taken together, these results suggest that CWJ-082 inhibits cell growth via mitotic arrest by activating the mitotic spindle checkpoint and by inducing α-tubulin polymerization and that these events ultimately lead to the apoptosis of human cervical cancer cells and inhibit tumor growth in HeLa xenograft mice.

Although glial cells play a major role in the pathogenesis of many neurological diseases by exacerbating neuronal and non-neuronal cell death, the mechanisms involved are unclear. We examined the effects of microglia-(MCM) or astrocyte-(ACM) conditioned media obtained by chemical ischemia on the neuronal injury in SH-SY5Y cells. Chemical ischemia was induced by the treatment with NaN(3) and 2-deoxy-d-glucose for 2h. MCM-treated SH-SY5Y cells showed reduced the viability, increased caspase-3 activity, decreased Bcl-2/Bax ratio, and increased cytochrome c release, increased inflammatory cytokines, and increased reactive oxygen species (ROS) generation. MCM also increased gp91phox nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which was inhibited by NADPH oxidase inhibitor, apocynin, and gp91phox siRNA. However, ACM did not show any significant changes. The results suggest that microglia activated by ischemic insult may increase reactive oxygen species generation via activation of gp91phox NADPH oxidase, resulting in neuronal injury., (Copyright 2009 Elsevier Inc. All rights reserved.)

Although donepezil, a potent acetylcholinesterase (AChE) inhibitor, has been used to treat Alzheimer's disease (AD) due to its neuroprotective effects, its mode of action to inhibit the growth of cancer cells is poorly understood. In the present study, we investigated the pro-apoptotic activities of donepezil in HL-60 human promyelocytic leukemia cells and the underlying molecular mechanism involved. It was found that donepezil induced the apoptosis of HL-60 and U937 cells in a dose- and time-dependent manner, as evidenced by the formation of DNA fragmentation and the accumulation of positive cells for Annexin V. In addition, the activations of caspase-8, -9, and -3 were significantly increased 36 h after donepezil treatment. Furthermore, the broad caspase inhibitor (z-VAD-fmk) blocked donepezil-induced apoptosis. In addition, donepezil was found to cause the loss of mitochondrial membrane potential (DeltaPsi(m)), to increase the release of cytochrome c to the cytosol, and to alter the expressions of Bcl-2 family proteins. Taken together, these results demonstrate for the first time that donepezil displayed an induction of apoptosis in HL-60 cells via a mitochondria-mediated caspase-dependent pathway.

In the present study, it was investigated whether 1,2-bis(2-aminophenoxy)ethane-N,N,N'N'-tetraacetic acid (BAPTA-AM), an intracellular Ca(2+) chelator, possesses protective effect against caffeine-induced apoptosis in the central nervous system. Through morphological and biochemical analyses, cells treated with caffeine exhibited several apoptotic features. On the other hand, cells treated with caffeine and BAPTA-AM, showed decreased occurrence of apoptotic features. In addition, it was shown that BAPTA-AM treatment inhibits caffeine-induced increase of caspase-3 enzyme activity. These results show that caffeine induces apoptotic death in human SK-N-MC neuroblastoma cells and BAPTA-AM prevents apoptosis by attenuating caffeine-induced caspase-3 activation.

Chronic inflammation is an underlying risk factor of colon cancer, and NF-κB plays a critical role in the development of inflammation-associated colon cancer in an AOM/DSS mouse model. The aim of this study was to determine whether the standardized ethanol extract obtained from the aerial parts of Artemisia princeps Pampanini cv. Sajabal (EAPP) is effective at preventing inflammation-associated colon cancer, and if so, to identify the signaling pathways involved. In the present study, protective efficacy of EAPP on tumor formation and the infiltrations of monocytes and macrophages in colons of an AOM/DSS mouse model were evaluated. It was found that colitis and tumor burdens showed statistically meaningful improvements after EAPP administration. Furthermore, these improvements were accompanied by a reduction in NF-κB activity and in the levels of NF-κB-dependent pro-survival proteins, that is, survivin, cFLIP, XIAP, and Bcl-2. In vitro , EAPP significantly reduced NF-κB activation and the levels of IL-1β and IL-8 mRNA and pro-survival proteins in HT-29 and HCT-116 colon cancer cells. Furthermore, EAPP caused caspase-dependent apoptosis. Based on these results, the authors suggest EAPP suppresses inflammatory responses and induces apoptosis partly via NF-κB inactivation, and that EAPP could be useful for the prevention of colitis-associated tumorigenesis. [ABSTRACT FROM AUTHOR]