PubMed · 14004259
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T WADA. 1962. [Recent antineoplastic agents].. https://pubmed.ncbi.nlm.nih.gov/14004259/
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Drug response differs substantially in cancer patients due to inter- and intra-tumor heterogeneity. Particularly, transcriptome context, especially tumor microenvironment, has been shown playing a significant role in shaping the actual treatment outcome. In this study, we develop a deep variational autoencoder (VAE) model to compress thousands of genes into latent vectors in a low-dimensional space. We then demonstrate that these encoded vectors could accurately impute drug response, outperform standard signature-gene based approaches, and appropriately control the overfitting problem. We apply rigorous quality assessment and validation, including assessing the impact of cell line lineage, cross-validation, cross-panel evaluation, and application in independent clinical data sets, to warrant the accuracy of the imputed drug response in both cell lines and cancer samples. Specifically, the expression-regulated component (EReX) of the observed drug response achieves high correlation across panels. Using the well-trained models, we impute drug response of The Cancer Genome Atlas data and investigate the features and signatures associated with the imputed drug response, including cell line origins, somatic mutations and tumor mutation burdens, tumor microenvironment, and confounding factors. In summary, our deep learning method and the results are useful for the study of signatures and markers of drug response.
Overexpression of cyclooxygenase (COX)-2 has been implicated in many pathologic conditions, including cancer. One practical inference of this finding is that sustained inhibition of COX-2 could serve as a promising target for prevention or therapy of cancer. Conventional nonsteroidal antiinflammatory drugs (NSAIDs) and recently developed COX-2-specific inhibitors have shown considerable promise in prevention of some forms of human cancer; however, its application is limited due to severe toxic side effects on normal cells. Therefore, there is a need to define novel, nontoxic dietary constituents with proven chemopreventive effects through other pathways that also possess COX-2 but not COX-1 inhibitory activity. Recent studies on green tea and its major polyphenolic constituent (-)epigallocatechin-3-gallate (EGCG) have established its remarkable cancer preventive and some cancer therapeutic effects. Here, we show that EGCG inhibits COX-2 without affecting COX-1 expression at both the mRNA and protein levels, in androgen-sensitive LNCaP and androgen-insensitive PC-3 human prostate carcinoma cells. Based on our study, it is tempting to suggest that a combination of EGCG with chemotherapeutic drugs could be an improved strategy for prevention and treatment of prostate cancer.
BACKGROUND: The specific inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, ZD1839 induces potent antitumoral effects on several advanced cancer types. The present study was undertaken to determine whether the combination of ZD1839 with an agent donating nitric oxide (NO(*)), sodium nitroprusside (SNP) results in a synergy of anticarcinogenic responses on metastatic prostate cancer (PC) cells. METHODS: The antiproliferative and apoptotic/necrotic effects of ZD1839 and SNP alone or in combination were estimated on EGF- and serum-stimulated LNCaP, DU145, and PC3 cells by MTT growth tests, trypan blue dye exclusion method, and flow cytometric analyses. Moreover, the cellular ceramide levels were evaluated by the diacylglycerol kinase enzymatic method and the amounts of cytosolic cytochrome c by ELISA assays. RESULTS: ZD1839 and SNP alone or in combination at lower concentrations induced an inhibition of EGF- and serum-stimulated growth of LNCaP, DU145, and PC3 concomitant with an arrest in the G1 phase of cellular cycle. Interestingly, the mixed ZD1839 and SNP also caused a more substantial apoptotic/necrotic death of these PC cells as compared to drugs alone. Moreover, we have observed that an inhibition of acidic sphingomyelinase, hydrogen peroxide (H(2)O(2)) accumulation and caspase cascades results in a significant reduction of apoptotic/necrotic death induced by mixed ZD1839 and SNP in EGF-stimulated PC3 cells. In addition, the combined ZD1839 plus SNP also induced a higher cellular ceramide and reactive oxygen species (ROS) production, mitochondrial transmembrane potential decrease, and cytochrome c amount released into cytosol as compared to drugs alone. CONCLUSIONS: The simultaneous use of EGFR inhibitor and compound releasing NO(*) might lead to a synergy in the ceramide and ROS production which might cause cellular membrane damages resulting in a massive apoptotic/necrotic death of metastatic PC cells.