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Targeted therapies and chemotherapies are prevalent in cancer treatment. Identification of predictive markers to stratify cancer patients who will respond to these therapies remains challenging because patient drug response data are limited. As large amounts of drug response data have been generated by cell lines, methods to efficiently translate cell-line-trained predictors to human tumors will be useful in clinical practice. Here, we propose versatile feature selection procedures that can be combined with any classifier. For demonstration, we combined the feature selection procedures with a (linear) logit model and a (nonlinear) K-nearest neighbor and trained these on cell lines to result in LogitDA and KNNDA, respectively. We show that LogitDA/KNNDA significantly outperforms existing methods, e.g., a logistic model and a deep learning method trained by thousands of genes, in prediction AUC (0.70-1.00 for seven of the ten drugs tested) and is interpretable. This may be due to the fact that sample sizes are often limited in the area of drug response prediction. We further derive a novel adjustment on the prediction cutoff for LogitDA to yield a prediction accuracy of 0.70-0.93 for seven drugs, including erlotinib and cetuximab, whose pathways relevant to anti-cancer therapies are also uncovered. These results indicate that our methods can efficiently translate cell-line-trained predictors into tumors. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 77-year old woman with soft tissue sarcomas (STS). She developed atypical fibroxanthoma in upper right extremity that involves antecubital fossa and upper arm. It mentions that a thoracodorsal artery perforator (TDAP) flap surgery was performed on the patient whole on a sitting position.

Background: Although targeted therapies have improved the clinical outcomes of cancer treatment, tumors resistance to targeted drug are often detected too late and cause mortality. CSE1L is secreted from tumor and its phosphorylation is regulated by ERK1/2. ERK1/2 is located downstream of various growth factor receptors and kinases, the targets of most targeted drugs. Serum phospho-CSE1L may be a marker for monitoring the efficacy of targeted therapy. Methods: We used mice tumor xenograft model to study the assay of serum phosphorylated CSE1L for early detecting the efficacy of targeted drugs. The phosphorylation status of CSE1L in vemurafenib and sorafenib treated tumor cells were assayed by immunoblotting with antibody against phosphorylated CSE1L. Results: Ras activation increased phospho-CSE1L expression in B16F10 melanoma cells. Vemurafenib and sorafenib treatment did not significantly reduce the total CSE1L levels; however, they inhibited ERK1/2 and CSE1L phosphorylation in A375 melanoma cells and HT-29 colorectal cancer cells. In the melanoma xenograft model, serum phospho- CSE1L level declined 5 days after vemurafenib/sunitinib treatment and 3 days after sorafenib/lapatinib treatment in the HT-29 colon cancer xenograft model. Vemurafenib/sunitinib and sorafenib/lapatinib treatments resulted in tumor regression. Conclusions: Our results indicated that serum phospho-CSE1L is useful for early detecting the efficacy of targeted therapy in initial treatment and for monitoring emerging secondary drug resistance to facilitate timely therapeutic decision making. [ABSTRACT FROM AUTHOR]

We revealed the cytotoxic effect of the flavonoid, fisetin (FIS), on human COLO205 colon cancer cells in the presence and absence of the HSP90 inhibitors, geldanamycin (GA) and radicicol (RAD). Compared to FIS treatment alone of COLO205 cells, GA and RAD significantly enhanced FIS-induced cytotoxicity, increased expression of cleaved caspase-3 and the PAPR protein, and produced a greater density of DNA ladder formation. GA and RAD also reduced the MMPs with induction of caspase-9 protein cleavage in FIS-treated COLO205 cells. Increased caspase-3 and -9 activities were detected in COLO205 cells treated with FIS+GA or FIS+RAD, and the intensity of DNA ladder formation induced by FIS+GA was reduced by adding the caspase-3 inhibitor, DEVD-FMK. A decrease in Bcl-2 but not Bcl-XL or Bax protein by FIS+GA or FIS+RAD was identified in COLO205 cells by Western blotting. A reduction in p53 protein with increased ubiquitin-tagged proteins was observed in COLO205 cells treated with FIS+GA or FIS+RAD. Furthermore, GA and RAD reduced the stability of the p53 protein in COLO205 cells under FIS stimulation. The evidence supports HSP90 inhibitors possibly sensitizing human colon cancer cells to FIS-induced apoptosis, and treating colon cancer by combining HSP90 inhibitors with FIS deserves further in vivo study. [ABSTRACT FROM AUTHOR]

An increase in MMP-9 gene expression and enzyme activity with stimulating the migration of GBM8401 glioma cells via wound healing assay by 12-O-tetradecanoylphorbol-13-acetate (TPA) was detected in glioblastoma cells GBM8401. TPA-induced translocation of protein kinase C (PKC)α from the cytosol to membranes, and migration of GBM8401 elicited by TPA was suppressed by adding the PKCα inhibitors, GF109203X and H7. Activation of extracellular signal-regulated kinase (ERK) and c-Jun-N-terminal kinase (JNK) by TPA was identified, and TPA-induced migration and MMP-9 activity was significantly blocked by ERK inhibitor PD98059 and U0126, but not JNK inhibitor SP600125. Activation of NF-κB protein p65 nuclear translocation and IκBα protein phosphorylation with increased NF-κB-directed luciferase activity by TPA were observed, and these were blocked by the PD98059 and IkB inhibitor BAY117082 accompanied by reducing migration and MMP-9 activity induced by TPA in GBM8401 cells. Transfection of GBM8401 cells with PKCα siRNA specifically reduced PKCα protein expression with blocking TPA-induced MMP-9 activation and migration. Additionally, suppression of TPA-induced PKCα/ERK/NK-κB activation, migration, and MMP-9 activation by flavonoids including kaempferol (Kae; 3,5,7,4′-tetrahydroxyflavone), luteolin (Lut; 5,7,3′4′-tetrahydroxyflavone), and wogonin (Wog; 5,7-dihydroxy-8-methoxyflavone) was demonstrated, and structure–activity relationship (SAR) studies showed that hydroxyl (OH) groups at C4′ and C8 are critical for flavonoids' action against MMP-9 enzyme activation and migration/invasion of glioblastoma cells elicited by TPA. Application of flavonoids to prevent the migration/invasion of glioblastoma cells through blocking PKCα/ERK/NF-κB activation is first demonstrated herein. J. Cell. Physiol. 225: 472–481, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Induction of 17β-estradiol (E2) and insulin-like growth factor-I (IGF-I) has been detected in breast carcinoma, however the interaction between E2 and IGF-I in the proliferation of breast carcinoma cells is still unclear. In the present study, we found that IGF-I enhances the E2-induced proliferation in MCF-7 human breast carcinoma cells in accordance with stimulation of colony formation via a soft agar assay. Activation of insulin receptor substrate-1 (IRS-1) protein and extracellular signal-related kinases (ERKs) and c-Jun N-terminal kinases (JNKs), but not p38 mitogen-activated protein kinase (MAPK), via phosphorylation induction was detected in MCF-7 cells treated with IGF-I plus E2 (E2/IGF-I). E2/IGF-I-induced proliferation was blocked by chemical inhibitors of ERKs (PD98059) and JNKs (SP600125). An increase in the expression of c-Jun protein was detected in E2/IGF-I-treated MCF-7 cells, and this was inhibited by PD98059 and SP600125. Transfection of the dominant negative MEKK and JNK plasmids significantly reduced E2/IGF-I-induced proliferation with suppression of c-Jun protein expression. An increase in peroxide production was detected in E2/IGF-I-treated cells, and N-acetyl-L-cysteine (NAC) and Tiron (TIR) addition significantly inhibited E2/IGF-I-induced cell proliferation with blocking of the phosphorylation of ERKs and JNKs, and the expression of c-Jun protein. Additionally, 3-OH flavone, baicalein, and quercetin showed effective inhibitory activities against E2/IGF-I-induced proliferation through suppressing proliferative events such as phosphorylation of IRS-1, ERKs, and JNKs proteins, and induction of c-Jun protein and colony formation. These results indicate that IGF-I interacts with E2 to promote the proliferation of breast carcinoma cells via ROS-dependent MAPK activation and c-Jun protein expression. The structure-related inhibition of E2/IGF-I-induced proliferative events by flavonoids is elucidated. J. Cell. Physiol. 212:666–674, 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Flavonoids including the aglycones, hesperetin (HT; 5,7,3′‐trihydroxy‐4′‐methoxy‐flavanone), and naringenin (NE; 5,7,4′‐trihydroxy flavanone) and glycones, hesperidin (HD; 5,7,3′‐trihydroxy‐4′‐methoxy‐flavanone 7‐rhamnoglucoside) and naringin (NI; 5,7,4′‐trihydroxy flavanone 7‐rhamno glucoside), were used to examine the importance of rutinose at C7 on the inhibitory effects of flavonoids on lipopolysaccharide (LPS)‐induced nitric oxide production in macrophages. Both HT and NE, but not their respective glycosides HD and NI, induced heme oxygenase 1 (HO‐1) protein expression in the presence or absence of LPS and showed time and dose‐dependent inhibition of LPS‐induced nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression in RAW264.7, J774A.1, and thioglycolate‐elicited peritoneal macrophages. Additive inhibitory effect of an HO‐1 inducer hemin and NE or NI on LPS‐induced NO production and iNOS expression was identified, and HO enzyme inhibitor tin protoporphyrin (SnPP) attenuated the inhibitory effects of HT, NE, and hemin on LPS‐induced NO production. Both NE and HT showed no effect on iNOS mRNA and protein stability in RAW264.7 cells. Removal of rutinose at C7 of HD and NI by enzymatic digestion using hesperidinase (HDase) and naringinase (NIase) produce inhibitory activity on LPS‐induced NO production, according to the production of the aglycones, HT and NE, by high‐performance liquid chromatography (HPLC) analysis. Furthermore, the amount of NO produced by LPS or lipoteichoic acid (LTA) was significantly reduced in HO‐1‐overexpressing cells (HO‐1/RAW264.7) compared to that in parental cells (RAW264.7). Results of the present study provide scientific evidence to suggest that rutinose at C7 is a negative moiety in flavonoid inhibition of LPS‐induced NO production, and that HO‐1 is involved in the inhibitory mechanism of flavonoids on LPS‐induced iNOS and NO production. © 2004 Wiley‐Liss, Inc. [ABSTRACT FROM AUTHOR]

We previously reported that adenovirus-mediated gene transfer of heme oxygenase-1 (HO-1) inhibits the development of atherosclerosis in apolipoprotein E-deficient mice. This finding implies that HO-1 induction is beneficial for protecting blood vessels. We also found that quercetin, a common polyphenolic compound in foods of plant origin, induces HO-1 expression in RAW264.7 cells. This study was aimed at examining the potency of quercetin as a HO-1 inducer and its regulation in rat aortic smooth muscle cells (RASMCs). We showed that quercetin-induced HO-1 production was in time- and dose-dependent fashions, and that this regulation occurred at both transcription and translation levels. Quercetin increased p38 mitogen-activated protein kinase (p38MAPK), but inhibited extracellular signal-regulated kinase in RASMCs. The level of quercetin-induced HO-1 expression was attenuated by SB202190 (a p38MAPK inhibitor). Taken together from the data in this study, we suggest that quercetin induced HO-1 expression, at least in part, through p38MAPK. [ABSTRACT FROM AUTHOR]

Epidermal growth factor (EGF) has been shown to induce proliferation in cells, however, the role of prostaglandin E2 (PGE2) plays in EGF-induced proliferation in still unclear. EGF and PGE2 showed proliferation responses in epidermoid carcinoma cell A431 by MTT and [3H] thymidine incorporation assay. Activation of the EGF receptor and extracellular signal-regulated protein kinases (ERK1/2), but not p38 and JNK, appeared 10 min after EGF treatment, whereas total amounts of ERK1/2, p38 and JNK remained unchanged in A431 cells, accompanied by induction of COX-2 and PGE2 production. PD98059, a specific ERK1/2 inhibitor, inhibited EGF-induced proliferation with concomitant decreases in ERK1/2 phosphorylation and COX-2/PGE2 induction. Non-steroid anti-inflammatory drugs (NSAIDs) such as aspirin and diclofenac, a COX activity inhibitor, inhibited EGF-induced proliferation by blocking PGE2 production. The addition of PGE2 reversed the inhibitory effects of PD98059, aspirin, and diclofenac on EGF-induced proliferation. This suggests that COX-2/PGE2 activation involves in EGF-induced proliferation and locates at the downstream of ERK1/2 activation. Furthermore, the natural product, 3-OH flavone, showed the most-potent inhibitory activity on EGF-induced proliferation among 9 structurally-related compounds, and suppression of EGF receptor phosphorylation, ERK1/2 phosphorylation, and COX-2/PGE2 production by 3-OH flavone was identified. PGE2 addition attenuates the inhibitory activity of 3-OH flavone on EGF-induced proliferation by MTT assay and colony formation by soft agar assay. Additionally, 3-OH flavone also showed more-specific inhibition on EGF- than on fetal bovine serum (FBS)-induced proliferation in A431 cells. Results of our present study provide evidence to demonstrate that PGE2 is an important downstream molecule in EGF-induced proliferation, and 3-OH flavone, which inhibits PGE2 production by blocking MAPK cascade, might reserve potential for development as an anti-cancer drug. © 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Quercetin (QUE; 3,5,7,3′,4′-tetrahydroxyflavone) has been shown to possess several beneficial biological activities including antitumor, anti-inflammation and antioxidant properties; however, the effects of QUE in preventing invasion by breast carcinoma cells are still undefined. Increases in the protein, messenger RNA and enzyme activity levels of matrix metalloproteinase (MMP)-9 were observed in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated MCF-7 cells, and these were blocked by QUE, but not by quercitrin or rutin. A translocation of protein kinase C (PKC)δ from the cytosol to the membrane followed by activation of extracellular signal-regulated kinase (ERK) and c-Jun/activator protein-1 (AP-1) by TPA was demonstrated, and TPA-induced MMP-9 activation and migration were inhibited by the pan PKC inhibitor, GF109203X, the specific PKCδ inhibitor, rottlerin, an ERK inhibitor (PD98059) and an AP-1 inhibitor (curcumin). Application of QUE significantly suppressed TPA-induced activation of the PKCδ/ERK/AP-1-signaling cascade. To elucidate the importance of hydroxyl (OH) substitutions to QUE’s inhibition of tumor migration, several structurally related flavones of QUE including 3′,4′-diOH, 3′,4′-diOCH3, 3,5,7-triOH, 3,4′,4′-triOH, 3,3′,4′-triOCH3, luteolin and fisetin were used. Results suggested that OH groups at both C3′ and C4′ play central roles in QUE’s inhibition of TPA-induced MMP-9 activation and migration, and an additional OH at C3, C5 or C7 may increase the inhibitory potency of the 3′,4′-diOH flavone against TPA-induced MMP-9 activity and migration. The antitumor invasion and migration effects of breast carcinoma cells induced by QUE with the structure–activity relationship analysis were identified. [ABSTRACT FROM AUTHOR]