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Resistance to chemotherapy is a challenging problem for treatment of cancer patients and autophagy has been shown to mediate development of resistance. In this study we systematically screened a library of 306 known anti-cancer drugs for their ability to induce autophagy using a cell-based assay. 114 of the drugs were classified as autophagy inducers; for 16 drugs, the cytotoxicity was potentiated by siRNA-mediated knock-down of Atg7 and Vps34. These drugs were further evaluated in breast cancer cell lines for autophagy induction, and two tyrosine kinase inhibitors, Sunitinib and Erlotinib, were selected for further studies. For the pharmacological inhibition of autophagy, we have characterized here a novel highly potent selective inhibitor of Vps34, SB02024. SB02024 blocked autophagy in vitro and reduced xenograft growth of two breast cancer cell lines, MDA-MB-231 and MCF-7, in vivo. Vps34 inhibitor significantly potentiated cytotoxicity of Sunitinib and Erlotinib in MCF-7 and MDA-MB-231 in vitro in monolayer cultures and when grown as multicellular spheroids. Our data suggests that inhibition of autophagy significantly improves sensitivity to Sunitinib and Erlotinib and that Vps34 is a promising therapeutic target for combination strategies in breast cancer.
This article was published in the following journal.
Name: Cancer letters
The clinical success of inhibitors targeting the PD-1/PD-L1 pathway has made this an active field in cancer immunotherapy. Currently, most drugs targeting this pathway are monoclonal antibodies. Small...
In response to stress, cancer cells generate nutrients and energy through a cellular recycling process called autophagy, which can promote survival and tumor progression. Accordingly, autophagy inhibi...
Due to the therapeutic potential of targeting protein-protein interactions (PPIs) there is a need for easily executed assays to perform high throughput screening (HTS) of inhibitors. We have developed...
The recent emergence of Zika virus, a mosquito-borne flavivirus, in the Americas has shed light on the severe neurological diseases associated with infection, notably congenital microcephaly in newbor...
Blockade the interaction of the programmed cell death protein 1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1) can prevent immune evasion of tumor cells and significantly prolong the surviva...
The purpose of this study is to evaluate the effect of small molecule therapy in primary cells derived from patients with lysosomal storage disease. The study will focus on activity of sma...
Autophagy is recognized as a central mechanism for the regulation of aging. . Osteoporosis (OA) and Alzheimer's disease (AD) are two forms of pathological aging, sometimes entangled, inclu...
In recent years, evidence has shown that mitochondrial dysfunction plays an important role in the development of age-related muscle decline that may lead to frailty. During aging, there i...
The goal of this pilot and feasibility study is to investigate the effects of a short course of metformin therapy on a surrogate marker of cellular senescence and autophagy among adult pat...
The purpose of this study is to examine the combination of one standard treatment for lung cancer plus an additional drug, hydroxychloroquine. The standard treatment for lung cancer being ...
A set of protein subcomplexes involved in PROTEIN SORTING of UBIQUITINATED PROTEINS into intraluminal vesicles of MULTIVESICULAR BODIES and in membrane scission during formation of intraluminal vesicles, during the final step of CYTOKINESIS, and during the budding of enveloped viruses. The ESCRT machinery is comprised of the protein products of Class E vacuolar protein sorting genes.
A 150 kDa protein serine-threonine kinase that is found as a regulatory subunit of the class III phosphatidylinositol 3-kinases. The protein is believed to play an important role in the regulation of vesicular trafficking with the cell.
Protein sorting signals that target proteins to PEROXISOMES.
An autophagy related protein that is similar to UBIQUITIN-ACTIVATING ENZYME E1. It functions in CYTOPLASM to VACUOLE transport (Cvt) and AUTOPHAGY by activating ATG12 PROTEIN for its conjugation with ATG5 PROTEIN, as well as the conjugation of ATG8 FAMILY PROTEINS with phosphatidylethanolamine for ATG8 association to Cvt vesicles and AUTOPHAGOSOME membranes. It is also required for the nitrogen starvation response in yeast, MITOPHAGY; and autophagic cell death induced by CASPASE 8 inhibition.
An autophagy-related protein that functions in AUTOPHAGOSOME biogenesis. It is conjugated to the ATG12 PROTEIN via a process that is similar to UBIQUITINATION and involves the ATG7 PROTEIN and ATG10 enzyme. The ATG12-ATG5 conjugate acts as an E3 UBIQUITIN LIGASE-like enzyme and is required for the localization of ATG8 PROTEINS to AUTOPHAGOSOME vesicle membranes and modification of membrane lipids.
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...
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Cancer is not just one disease but many diseases. There are more than 100 different types of cancer. Most cancers are named for the organ or type of cell in which they start - for example, cancer that begins in the colon is called colon cancer; cancer th...