Abrogation of ATR function preferentially augments cisplatin-induced cytotoxicity in PTEN-deficient breast cancer cells.

Targeting replication stress response is currently emerging as new therapeutic strategy for cancer treatment, based on monotherapy and combination approaches. As a key sensor in response to DNA damage, ataxia telangiectasia and rad3-related (ATR) kinase has become a potential therapeutic target as tumor cells are to rely heavily on ATR for survival. The tumor suppressor phosphatase and tensin homolog (PTEN) plays a crucial role in maintaining chromosome integrity.

Combination of DESI2 and endostatin gene therapy significantly improves antitumor efficacy by accumulating DNA lesions, inducing apoptosis and inhibiting angiogenesis.

DESI2 is a novel pro-apoptotic gene. We previously reported that DESI2 overexpression induces S phase arrest and apoptosis by activating checkpoint kinases. This work was to test whether the combination of endostatin, an endogenous antiangiogenic inhibitor, with DESI2 could improve the therapy efficacy in vitro and in vivo.

hPNAS-4 inhibits proliferation through S phase arrest and apoptosis: underlying action mechanism in ovarian cancer cells.

PNAS-4, a novel pro-apoptotic gene, was activated during the early response to DNA damage. Previous studies have shown that hPNAS-4 can inhibit tumor growth when over-expressed in ovarian cancer cells. However, the underlying action mechanism remains elusive.

Enhanced gemcitabine-mediated cell killing of human lung adenocarcinoma by vector-based RNA interference against PLK1.

Specific PLK1 silencing may be an effective gene therapy modality of treating PLK1-overexpressed cancers. In this study, we first explored the anticancer efficacy of three different short hairpin-expressing plasmids targeting PLK1 in animal model, and then determined the combination therapy effect of gemcitabine with PLK1-shRNA as an adjuvant. Transfection of the PLK1-shRNAs to A549 lung cancer cells induced significant PLK1 depletion, growth inhibition and apoptosis.

NOXA-induced alterations in the Bax/Smac axis enhance sensitivity of ovarian cancer cells to cisplatin.

Ovarian cancer is the most common cause of death from gynecologic malignancy. Deregulation of p53 and/or p73-associated apoptotic pathways contribute to the platinum-based resistance in ovarian cancer. NOXA, a pro-apoptotic BH3-only protein, is identified as a transcription target of p53 and/or p73.

Noxa enhances the cytotoxic effect of gemcitabine in human ovarian cancer cells.

Noxa is an important proapoptotic protein in the intrinsic pathway of cell apoptosis. Experiments were carried out to investigate whether Noxa could, therefore, enhance the cytotoxic effect of gemcitabine in human ovarian cancer cell lines (A2780 and COC1). In this study, the combined treatment of Noxa and gemcitabine, in vitro, significantly inhibited the proliferation of A2780 and COC1 cells, as verified by MTT assay, Hoechst staining, and flow cytometric analysis.

The p53 upregulated modulator of apoptosis (PUMA) chemosensitizes intrinsically resistant ovarian cancer cells to cisplatin by lowering the threshold set by Bcl-x(L) and Mcl-1.

Ovarian cancer is the number one cause of death from gynecologic malignancy. A defective p53 pathway is a hallmark of ovarian carcinoma. The p53 mutation correlates significantly with resistance to platinum-based chemotherapy, early relapse and shortened overall survival in ovarian cancer patients.

Induction of tumor inhibition and apoptosis by a candidate tumor suppressor gene DRR1 on 3p21.1.

Down-regulated in renal cell carcinoma gene (DRR1) is one of the candidate tumor suppressor genes (TSGs) on human 3p21.1. This study was performed to validate the expression status of DRR1 gene in cancer cells and the expression pattern of the protein in clinical specimens of human lung cancer and to examine its potential as a molecular target for treatment of lung cancer in vivo.

Formaldehyde at low concentration induces protein tau into globular amyloid-like aggregates in vitro and in vivo.

Recent studies have shown that neurodegeneration is closely related to misfolding and aggregation of neuronal tau. Our previous results show that neuronal tau aggregates in formaldehyde solution and that aggregated tau induces apoptosis of SH-SY5Y and hippocampal cells. In the present study, based on atomic force microscopy (AFM) observation, we have found that formaldehyde at low concentrations induces tau polymerization whilst acetaldehyde does not.

Amyloid-like aggregates of neuronal tau induced by formaldehyde promote apoptosis of neuronal cells.

Background: The microtubule associated protein tau is the principle component of neurofibrillar tangles, which are a characteristic marker in the pathology of Alzheimer's disease; similar lesions are also observed after chronic alcohol abuse. Formaldehyde is a common environmental contaminant and also a metabolite of methanol. Although many studies have been done on methanol and formaldehyde intoxication, none of these address the contribution of protein misfolding to the pathological mechanism, in particular the effect of formaldehyde on protein conformation and polymerization.

Changes in conformation of human neuronal tau during denaturation in formaldehyde solution.

Human neuronal tau was incubated in formaldehyde solution at low concentrations and the intensity of light scattering of tau-40 solution at 480 nm increased markedly. Then potassium iodide was used to quench the intrinsic fluorescence of tau. The fluorescent quenching constants decreased as formaldehyde concentrations increased.

Neuronal tau induces DNA conformational changes observed by atomic force microscopy.

Neuronal tau associates with chromosome scaffold and localizes in the nuclear and the nucleolar organization regions in neuronal and some non-neuronal cells. Observing the interaction of neuronal tau with DNA under AFM shows that tau binds to DNA as a monomer, and tau-DNA complex forms a beads-on-a-string structure when the mass ratio is 1:10 (molar ratio of tau/DNA approximately 1:700 bp). A beads-on-a-coil structure, in which tau is as polymers, will appear when the mass ratio is up to 1:5 (molar ratio of tau/DNA approximately 1:350 bp).

Chaperone-like manner of human neuronal tau towards lactate dehydrogenase.

In our experiments, inactivation of lactate dehydrogenase (LDH, EC1.1.1.