- Anti-inflammatory drug resistance selects putative cancer stem cells in a cellular model for genetically predisposed colon cancer. [Journal Article]
- OLOncol Lett 2018; 15(1):642-648
- Mutations in the adenomatous polyposis coli (Apc) tumor suppressor gene represent the primary genetic defect in colon carcinogenesis. Apc+/- mouse models exhibit pre-invasive small intestinal adenoma...
Mutations in the adenomatous polyposis coli (Apc) tumor suppressor gene represent the primary genetic defect in colon carcinogenesis. Apc+/- mouse models exhibit pre-invasive small intestinal adenomas. Cell culture models exhibiting Apc defects in the colon and quantifiable cancer risk provide a novel clinically relevant approach. The tumor-derived Apc-/- colonic epithelial cell line 1638N COL-Pr1 represented the experimental model. The anti-inflammatory drugs sulindac (SUL) and celecoxib (CLX) represented the test compounds. Compared with non-tumorigenic Apc+/+ C57COL cells, the Apc+/- 1638N COL cells and Apc-/- 1638N COL-Pr1 cells exhibited progressive loss of homeostatic growth control. Compared with Apc+/- cells, Apc-/- cells displayed increased expression of biomarkers specific for hyper-proliferation. Treatment of Apc-/- cells with SUL and CLX resulted in inhibition of anchorage-independent colony formation in vitro, which is indicative of reduced cancer risk in vivo. Mechanistically, SUL and CLX suppressed the expression of the Apc target genes β-catenin, cyclin D1, c-Myc and cyclooxygenase-2. Long-term treatment with high concentrations of SUL and CLX led to the selection of hyper-proliferative drug-resistant phenotypes. The Apc-/- SUL-resistant phenotype displayed spheroid formation and enhanced the expression of the stem cell-specific molecular markers CD44, CD133 and c-Myc. These data demonstrated the growth-inhibitory efficacy of SUL and CLX and indicated that drug resistance leads to the selection of a putative cancer stem cell phenotype. The study outcome validates a stem cell-targeted mechanistic approach to identify testable alternative leads for chemotherapy-resistant colon cancer.
- Association of Sulindac and Erlotinib vs Placebo With Colorectal Neoplasia in Familial Adenomatous Polyposis: Secondary Analysis of a Randomized Clinical Trial. [Journal Article]
- JOJAMA Oncol 2018 Feb 08
- CONCLUSIONS: In this double-blind, placebo-controlled, randomized trial we showed that combination treatment with sulindac and erlotinib compared with placebo resulted in significantly lower colorectal polyp burden after 6 months of treatment. There was a reduction in polyp burden in both those with an entire colorectum and those with only a rectal pouch or rectum.
- Palladium/PC-Phos-Catalyzed Enantioselective Arylation of General Sulfenate Anions: Scope and Synthetic Applications. [Journal Article]
- JAJ Am Chem Soc 2018 Feb 20
- Herein we reported an efficient palladium-catalyzed enantioselective arylation of both alkyl and aryl sulfenate anions to deliver various chiral sulfoxides in good yields (up to 98%) with excellent e...
Herein we reported an efficient palladium-catalyzed enantioselective arylation of both alkyl and aryl sulfenate anions to deliver various chiral sulfoxides in good yields (up to 98%) with excellent enantioselectivities (up to 99% ee) by the use of our developed chiral O,P-ligands (PC-Phos). PC-Phos are easily prepared in short steps from inexpensive commercially available starting materials. The single-crystal structure of the PC4/PdCl2showed that a rarely observed 11-membered ring was formed via the O,P-coordination with the palladium(II) center. The salient features of this method include general substrate scope, ease of scale-up, applicable to the late-stage modification of bioactive compounds, and the synthesis of a marketed medicine Sulindac.
- Pazopanib therapy for desmoid tumors in adolescent and young adult patients. [Journal Article]
- PBPediatr Blood Cancer 2018 Jan 31
- CONCLUSIONS: Pazopanib provides a promising, well-tolerated therapy for DT/AF in the AYA population and warrants further study.
- Is it all said for NSAIDs in Alzheimer's disease? Role of mitochondrial calcium uptake. [Journal Article]
- CACurr Alzheimer Res 2017 Dec 27
- Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Unfortunately, recent trials have failed in providing compelling evidenc...
Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Unfortunately, recent trials have failed in providing compelling evidence of neuroprotection. Discussion as to why NSAIDs effectivity is uncertain is ongoing. Possible explanations include the view that NSAIDs and other possible disease-modifying drugs should be provided before the patients develop symptoms of AD or cognitive decline. In addition, NSAID targets for neuroprotection are unclear. Both COX-dependent and independent mechanisms have been proposed, including γ-secretase that cleaves the amyloid precursor protein (APP) and yields amyloid β peptide (Aβ). We have proposed a neuroprotection mechanism for NSAIDs based on inhibition of mitochondrial Ca2+ overload. Aβ oligomers promote Ca2+ influx and mitochondrial Ca2+ overload leading to neuron cell death. Several non-specific NSAIDs including ibuprofen, sulindac, indomethacin and R-flurbiprofen depolarize mitochondria in the low µM range and prevent mitochondrial Ca2+ overload induced by Aβ oligomers and/or N-methyl-D-aspartate (NMDA). However, at larger concentrations, NSAIDs may collapse mitochondrial potential (ΔΨ) leading to cell death. Accordingly, this mechanism may explain neuroprotection at low concentrations and damage at larger doses, thus providing clues on the failure of promising trials. Perhaps lower NSAID concentrations and/or alternative compounds with larger dynamic ranges should be considered for future trials to provide definitive evidence of neuroprotection against AD.
- Autophagy: novel applications of nonsteroidal anti-inflammatory drugs for primary cancer. [Review]
- CMCancer Med 2018; 7(2):471-484
- In eukaryotic cells, autophagy is a process associated with programmed cell death. During this process, cytoplasmic proteins and organelles are engulfed by double-membrane autophagosomes, which then ...
In eukaryotic cells, autophagy is a process associated with programmed cell death. During this process, cytoplasmic proteins and organelles are engulfed by double-membrane autophagosomes, which then fuse with lysosomes to form autolysosomes. These autolysosomes then degrade their contents to recycle the cellular components. Autophagy has been implicated in a wide variety of physiological and pathological processes that are closely related to tumorigenesis. In recent years, an increasing number of studies have indicated that nonsteroidal anti-inflammatory drugs, such as celecoxib, meloxicam, sulindac, aspirin, sildenafil, rofecoxib, and sodium salicylate, have diverse effects in cancer that are mediated by the autophagy pathway. These nonsteroidal anti-inflammatory drugs can modulate tumor autophagy through the PI3K/Akt/mTOR, MAPK/ERK1/2, P53/DRAM, AMPK/mTOR, Bip/GRP78, CHOP/ GADD153, and HGF/MET signaling pathways and inhibit lysosome function, leading to p53-dependent G1 cell-cycle arrest. In this review, we summarize the research progress in autophagy induced by nonsteroidal anti-inflammatory drugs and the molecular mechanisms of autophagy in cancer cells to provide a reference for the potential benefits of nonsteroidal anti-inflammatory drugs in cancer chemotherapy.
- Molecular Predicators of Duodenal Familial Adenomatous Polyposis Chemoprevention: Do Chemopreventive Drugs Hit Their Presumed Molecular Targets? [Editorial]
- CPCancer Prev Res (Phila) 2018; 11(1):1-3
- Patients with familial adenomatous polyposis (FAP) have an increased risk of developing duodenal adenomas and adenocarcinomas. In previous trials, sulindac (a cyclooxygenase inhibitor) alone failed t...
Patients with familial adenomatous polyposis (FAP) have an increased risk of developing duodenal adenomas and adenocarcinomas. In previous trials, sulindac (a cyclooxygenase inhibitor) alone failed to significantly suppress duodenal tumorigenesis in FAP patients, but sulindac plus the tyrosine kinase inhibitor erlotinib significantly reduced duodenal polyp burden. Delker and colleagues report in this issue (beginning on page 4) on transcriptome analyses that aimed to identify the molecular targets mediating the response to sulindac-erlotinib. Their exploratory transcriptome analyses suggested that sulindac-erlotinib suppressed duodenal polyposis via inhibiting Wnt/β-catenin, EGFR, and cyclooxygenase pathways. This perspective discusses the significance and limitations of the study.Cancer Prev Res; 11(1); 1-3. ©2017 AACRSee related article by Delker et al., p. 4.
- Differential preventive activity of sulindac and atorvastatin in Apc+/Min-FCCCmice with or without colorectal adenomas. [Journal Article]
- GutGut 2017 Nov 09
- CONCLUSIONS: The tumour status of animals at treatment initiation dictates response to therapeutic intervention. Atorvastatin eliminated microadenomas in tumour-free mice. The tumour inhibition observed with Sul/Atorva in tumour-bearing mice was greater than that achieved with each agent.
- Does MutatedK-RASOncogene Attenuate the Effect of Sulindac in Colon Cancer Chemoprevention? [Journal Article]
- CPCancer Prev Res (Phila) 2018; 11(1):16-26
- The NSAID sulindac has been successfully used alone or in combination with other agents to suppress colon tumorigenesis in patients with genetic predisposition and also showed its efficacy in prevent...
The NSAID sulindac has been successfully used alone or in combination with other agents to suppress colon tumorigenesis in patients with genetic predisposition and also showed its efficacy in prevention of sporadic colon adenomas. At the same time, some experimental and clinical reports suggest that a mutantK-RASoncogene may negate sulindac antitumor efficacy. To directly assess sulindac activity at suppressing premalignant lesions carrying K-RAS mutation, we utilized a novel mouse model with an inducible colon-specific expression of the mutantK-rasoncogene (K-rasG12D). Tumor development and treatment effects were monitored by minimally invasive endoscopic Optical coherence tomography. Expression of the mutantK-rasallele accelerated azoxymethane (AOM)-induced colon carcinogenesis in C57BL/6 mice, a strain otherwise resistant to this carcinogen. Sulindac completely prevented AOM-induced tumor formation inK-raswild-type (K-raswt) animals. InK-rasG12D-mutant mice, a 38% reduction in tumor number, an 83% reduction in tumor volume (P≤ 0.01) and an increase in the number of adenoma-free mice (P= 0.04) were observed. The partial response ofK-RasG12Danimals to sulindac treatment was evident by the decrease in mucosal thickness (P< 0.01) and delay in progression of the precancerous aberrant crypt foci to adenomas. Molecular analyses showed significant induction in cyclooxygenase 2 (COX-2), cleaved caspase-3 (CC3), and Ki-67 expression by AOM, but not sulindac treatment, in all genotypes. Our data underscore the importance of screening forK-RASmutations in individuals with colon polyps to provide more personalized interventions targeting mutantK-RASsignaling pathways.Cancer Prev Res; 11(1); 16-26. ©2017 AACR.
New Search Next
- Chemoprevention with Cyclooxygenase and Epidermal Growth Factor Receptor Inhibitors in Familial Adenomatous Polyposis Patients: mRNA Signatures of Duodenal Neoplasia. [Journal Article]
- CPCancer Prev Res (Phila) 2018; 11(1):4-15
- To identify gene expression biomarkers and pathways targeted by sulindac and erlotinib given in a chemoprevention trial with a significant decrease in duodenal polyp burden at 6 months (P< 0.001) in ...
To identify gene expression biomarkers and pathways targeted by sulindac and erlotinib given in a chemoprevention trial with a significant decrease in duodenal polyp burden at 6 months (P< 0.001) in familial adenomatous polyposis (FAP) patients, we biopsied normal and polyp duodenal tissues from patients on drug versus placebo and analyzed the RNA expression. RNA sequencing was performed on biopsies from the duodenum of FAP patients obtained at baseline and 6-month endpoint endoscopy. Ten FAP patients on placebo and 10 on sulindac and erlotinib were selected for analysis. Purity of biopsied polyp tissue was calculated from RNA expression data. RNAs differentially expressed between endpoint polyp and paired baseline normal were determined for each group and mapped to biological pathways. Key genes in candidate pathways were further validated by quantitative RT-PCR. RNA expression analyses of endpoint polyp compared with paired baseline normal for patients on placebo and drug show that pathways activated in polyp growth and proliferation are blocked by this drug combination. Directly comparing polyp gene expression between patients on drug and placebo also identified innate immune response genes (IL12 and IFNγ) preferentially expressed in patients on drug. Gene expression analyses from tissue obtained at endpoint of the trial demonstrated inhibition of the cancer pathways COX2/PGE2, EGFR, and WNT. These findings provide molecular evidence that the drug combination of sulindac and erlotinib reached the intended tissue and was on target for the predicted pathways. Furthermore, activation of innate immune pathways from patients on drug may have contributed to polyp regression.Cancer Prev Res; 11(1); 4-15. ©2017 AACRSee related editorial by Shureiqi, p. 1.