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Cancer Prevention Research... Aug 2022Obesity is associated with an increased risk of colon cancer. Our current study examines whether weight loss and/or treatment with the NSAID sulindac suppresses the...
UNLABELLED
Obesity is associated with an increased risk of colon cancer. Our current study examines whether weight loss and/or treatment with the NSAID sulindac suppresses the protumor effects of obesity in a mouse model of colon cancer. Azoxymethane-treated male FVB/N mice were fed a low-fat diet (LFD) or high-fat diet (HFD) for 15 weeks, then HFD mice were randomized to remain on HFD (obese) or switch to LFD [formerly obese (FOb-LFD)]. Within the control (LFD), obese, and FOb-LFD groups, half the mice started sulindac treatment (140 ppm in the diet). All mice were euthanized 7 weeks later. FOb-LFD mice had intermediate body weight levels, lower than obese but higher than control (P < 0.05). Sulindac did not affect body weight. Obese mice had greater tumor multiplicity and burden than all other groups (P < 0.05). Transcriptomic profiling indicated that weight loss and sulindac each modulate the expression of tumor genes related to invasion and may promote a more antitumor immune landscape. Furthermore, the fecal microbes Coprobacillus, Prevotella, and Akkermansia muciniphila were positively correlated with tumor multiplicity and reduced by sulindac in obese mice. Coprobacillus abundance was also decreased in FOb-LFD mice. In sum, weight loss and sulindac treatment, alone and in combination, reversed the effects of chronic obesity on colon tumor multiplicity and burden. Our findings suggest that an investigation regarding the effects of NSAID treatment on colon cancer risk and/or progression in obese individuals is warranted, particularly for those unable to achieve moderate weight loss.
PREVENTION RELEVANCE
Obesity is a colon cancer risk and/or progression factor, but the underlying mechanisms are incompletely understood. Herein we demonstrate that obesity enhances murine colon carcinogenesis and expression of numerous tumoral procancer and immunosuppressive pathways. Moreover, we establish that weight loss via LFD and/or the NSAID sulindac mitigate procancer effects of obesity.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Colonic Neoplasms; Diet, High-Fat; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Microbiota; Obesity; Sulindac; Transcriptome; Weight Loss
PubMed: 35653548
DOI: 10.1158/1940-6207.CAPR-21-0531 -
Gut Feb 2023Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal adenomas and cancer. Combination sulindac and erlotinib was previously...
IMPORTANCE
Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal adenomas and cancer. Combination sulindac and erlotinib was previously shown to reduce duodenal polyp burden but was associated with a relatively high adverse event (AE) rate.
OBJECTIVE
To evaluate if a once weekly dosing schedule for erlotinib intervention improves the AE profile, while still providing efficacy with respect to reduced polyp burden, in participants with FAP.
DESIGN, SETTING AND PARTICIPANTS
Single-arm trial, enrolling 46 participants with FAP, conducted from October 2017 to September 2019 in eight academic cancer centres.
EXPOSURES
Participants self-administered 350 mg of erlotinib by mouth, one time per week for 6 months.
MAIN OUTCOMES AND MEASURES
Duodenal polyp burden (sum of polyp diameters) was assessed in the proximal duodenum by esophagogastroduodenoscopy performed at baseline and 6 months, with mean per cent change defined as the primary efficacy outcome of interest. Rate of grade 2-3 AEs was evaluated as a co-primary outcome. Secondary outcomes included changes in total duodenal polyp count, along with changes in lower gastrointestinal (GI) polyp burden and count (for participants examined by optional lower endoscopy).
RESULTS
Forty-six participants (mean age, 44.1 years (range, 18-68); women, 22 (48%)) were enrolled; 42 participants completed 6 months of intervention and were included in the per-protocol analysis. Duodenal polyp burden was significantly reduced after 6 months of weekly erlotinib intervention, with a mean per cent change of -29.6% (95% CI, -39.6% to -19.7%; p<0.0001). Similar results were observed in subgroup analyses defined by participants with advanced duodenal polyposis (Spigelman 3) at baseline (mean, -27%; 95% CI, -38.7% to -15.2%; p<0.0001). Post-intervention Spigelman stage was downstaged in 12% of the participants. Lower GI polyp number was also decreased after 6 months of intervention (median, -30.8%; IQR, -47.4% to 0.0%; p=0.0256). Grade 2 or 3 AEs were reported in 71.7% of subjects, with only two experiencing grade 3 toxicity at least possibly related to intervention.
CONCLUSION
In this single-arm, multi-centre trial of participants with FAP, erlotinib one time per week resulted in markedly lower duodenal polyp burden, and modestly reduced lower GI polyp burden, after 6 months of intervention. While AEs were still reported by nearly three-quarters of all participants, these events were generally lower grade and well-tolerated. These findings support further investigation of erlotinib as an effective, acceptable cancer preventive agent for FAP-associated GI polyposis.
TRIAL REGISTRATION NUMBER
NCT02961374.
Topics: Humans; Female; Adult; Erlotinib Hydrochloride; Adenomatous Polyposis Coli; Duodenal Neoplasms; Duodenum; Endoscopy, Gastrointestinal
PubMed: 35636921
DOI: 10.1136/gutjnl-2021-326532 -
Journal of Clinical Medicine May 2022We report a retrospective case series of six Hispanic children with tumors treated with metronomic chemotherapy. The six cases comprised one rhabdoid tumor of the... (Review)
Review
We report a retrospective case series of six Hispanic children with tumors treated with metronomic chemotherapy. The six cases comprised one rhabdoid tumor of the kidney, one ependymoma, two medulloblastomas, one neuroblastoma, and a type II neurocytoma of the spine. Treatment included oral cyclophosphamide daily for 21 days alternating with oral etoposide daily for 21 days in a backbone of daily valproic acid and celecoxib. In one case, celecoxib was substituted with sulindac. Of the six patients, three showed complete responses, and all patients showed some response to metronomic therapy with only minor hematologic toxicity. One patient had hemorrhagic gastritis likely associated with NSAIDs while off prophylactic antacids. These data add to a growing body of evidence suggesting that continuous doses of valproic acid and celecoxib coupled with alternating metronomic chemotherapy of agents such as etoposide and cyclophosphamide can produce responses in pediatric tumors relapsing to conventional dose chemotherapy.
PubMed: 35628975
DOI: 10.3390/jcm11102849 -
Frontiers in Public Health 2022Given the rapidly changing political rhetoric and policies concerning immigration, and the likely impact of this rhetoric on immigrants' adjustment, it is essential to...
Given the rapidly changing political rhetoric and policies concerning immigration, and the likely impact of this rhetoric on immigrants' adjustment, it is essential to understand the experiences of recently arrived immigrant individuals and families. This article describes methods to recruit and retain recently arrived Hispanic families in longitudinal research and clinical practice. Barriers to continued engagement with recent-immigrant families include residential mobility, wariness toward authority figures (including researchers and practitioners), and unpredictable work schedules. These barriers can lead to challenges related to recruitment/engagement, logistics, establishing trust, and retention. This article describes decisions made, experiences, and lessons learned in a longitudinal study of Hispanic families in two cities. We also provide implications for clinical practice.
Topics: Emigrants and Immigrants; Emigration and Immigration; Hispanic or Latino; Humans; Longitudinal Studies; Sulindac
PubMed: 35602133
DOI: 10.3389/fpubh.2022.879101 -
Case Reports in Oncology 2022Desmoid tumors are clonal fibroblastic neoplasms that arise in soft tissues. Patients with familial adenomatous polyposis (FAP) can develop intra-abdominal desmoid...
Desmoid tumors are clonal fibroblastic neoplasms that arise in soft tissues. Patients with familial adenomatous polyposis (FAP) can develop intra-abdominal desmoid tumors. However, metachronous appearance of intra-abdominal desmoid tumor is rare, and its clinical course is not well known. Here, we report a case of spontaneous regression of metachronous intra-abdominal desmoid tumor in a 36-year-old man with FAP. The patient was diagnosed with FAP and underwent laparoscopic total colorectomy. Intra-abdominal desmoid tumor appeared 2 years later and progressed despite treatment with tamoxifen and sulindac. He received four cycles of combinatory therapy with dacarbazine and adriamycin, resulting in shrinkage and stabilization of the desmoid tumor even after cessation of chemotherapy. A new intra-abdominal desmoid tumor developed 2 years later at a different site from the first lesion and progressed from 65 mm to 70 mm in diameter within a month. The size of the first lesion, however, remained unchanged. We prepared for chemotherapy because the second lesion progressed, but follow-up computed tomography showed spontaneous shrinkage of the second lesion. The patient still has not needed additional therapy as of more than 4 years after the appearance of the second lesion. Immunohistochemical staining showed the presence of macrophages in the second lesion. Although metachronous intra-abdominal desmoid tumor is rare and management protocols have yet to be established, this case suggests that an active surveillance approach may be applicable under careful follow-up in asymptomatic patients.
PubMed: 35350802
DOI: 10.1159/000521920 -
Breast Cancer Research and Treatment Feb 2022To examine benefit of sulindac for relief of musculoskeletal symptoms (MSS) in patients stable on aromatase inhibitors (AIs).
PURPOSE
To examine benefit of sulindac for relief of musculoskeletal symptoms (MSS) in patients stable on aromatase inhibitors (AIs).
METHODS
Sulindac was evaluated at 150 mg twice daily for effects on MSS at 3, 6, 9, and 12 months in 50 postmenopausal women stable on AI therapy for a median of 12.5 months for hormone receptor-positive breast cancer. A separate, non-randomized group of 50 similar patients was observed for change in MSS over 12 months. MSS severity was assessed using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index and Brief Pain Inventory Short Form (BPI-SF). The Functional Assessment of Cancer Therapy-General form (FACT-G) measured quality of life (QOL). Change in MSS and QOL across time was assessed in each group using linear mixed effects models.
RESULTS
Stiffness, not pain, was the main complaint at baseline. At 12 months, sulindac patients reported decreases (improvements) in mean (95% CI) Total WOMAC score [- 5.85 (- 9.73, - 1.96)] and WOMAC pain [- 5.40 (- 10.64, - 0 .18)], Stiffness [- 9.53 (- 14.98, - 4.08)] and Physical Function [- 5.61 (- 9.62, - 1.60)] subscales, but not BPI-SF worst pain. Among sulindac patients with higher baseline MSS severity, 35% experienced ≥ 50% improvement in Total WOMAC and Total FACT-G scores [6.18 (2.08, 10.27); P = 0.003]. For the observation group, MSS and QOL did not improve over 12 months, even among those with higher baseline MSS severity.
CONCLUSIONS
Sulindac may relieve MSS in AI patients, especially physical function and stiffness. Randomized controlled trials should further evaluate NSAIDs on AI-MSS and AI adherence.
TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION
NCT01761877, December, 2012.
Topics: Aromatase Inhibitors; Breast Neoplasms; Female; Humans; Pain; Quality of Life; Sulindac; Treatment Outcome
PubMed: 35039952
DOI: 10.1007/s10549-021-06485-0 -
BMC Pharmacology & Toxicology Jan 2022Pain relief remains a major subject of inadequately met need of patients. Therapeutic agents designed to treat pain and inflammation so far have low to moderate...
BACKGROUND
Pain relief remains a major subject of inadequately met need of patients. Therapeutic agents designed to treat pain and inflammation so far have low to moderate efficiencies with significant untoward side effects. FAAH-1 has been proposed as a promising target for the discovery of drugs to treat pain and inflammation without significant adverse effects. FAAH-1 is the primary enzyme accountable for the degradation of AEA and related fatty acid amides. Studies have revealed that the simultaneous inhibition of COX and FAAH-1 activities produce greater pharmacological efficiency with significantly lowered toxicity and ulcerogenic activity. Recently, the metabolism of endocannabinoids by COX-2 was suggested to be differentially regulated by NSAIDs.
METHODS
We analysed the affinity of oleamide, arachidonamide and stearoylamide at the FAAH-1 in vitro and investigated the potency of selected NSAIDs on the hydrolysis of endocannabinoid-like molecules (oleamide, arachidonamide and stearoylamide) by FAAH-1 from rat liver. NSAIDs were initially screened at 500 μM after which those that exhibited greater potency were further analysed over a range of inhibitor concentrations.
RESULTS
The substrate affinity of FAAH-1 obtained, increased in a rank order of oleamide < arachidonamide < stearoylamide with resultant V values in a rank order of arachidonamide > oleamide > stearoylamide. The selected NSAIDs caused a concentration-dependent inhibition of FAAH-1 activity with sulindac, carprofen and meclofenamate exhibiting the greatest potency. Michaelis-Menten analysis suggested the mode of inhibition of FAAH-1 hydrolysis of both oleamide and arachidonamide by meclofenamate and indomethacin to be non-competitive in nature.
CONCLUSION
Our data therefore suggest potential for study of these compounds as combined FAAH-1-COX inhibitors.
Topics: Amidohydrolases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acids; Enzyme Inhibitors; Fatty Acids; Humans; Polyunsaturated Alkamides; Rats
PubMed: 34983657
DOI: 10.1186/s40360-021-00539-1 -
Journal of Ocular Pharmacology and... 2022Dry eye disease (DED) is classified as aqueous deficient, evaporative, or mixed. We investigated the therapeutic effect of the novel anti-inflammatory drug...
Dry eye disease (DED) is classified as aqueous deficient, evaporative, or mixed. We investigated the therapeutic effect of the novel anti-inflammatory drug phosphosulindac (PS) in rabbit models of DED encompassing its pathogenesis, and its transition to chronicity. We treated three rabbit models of DED with PS (hydrogel formulation) or vehicle topically applied 1 × /day. We induced aqueous-deficient DED (acute and chronic) by injecting Concanavalin A into lacrimal glands; evaporative DED by injecting into the upper eyelid inactivated in complete Freund's adjuvant; and mixed DED through desiccative stress, induced by holding open the eye for 3 h. We determined corneal sensitivity, tear break-up time (TBUT), Schirmer's tear test (STT), tear osmolality, and fluorescein staining of the ocular surface. PS reversed all abnormal DED parameters. In acute DED, PS dose dependently normalized corneal sensitivity and tear osmolality; and improved TBUT, STT, and fluorescein staining. PS normalized corneal sensitivity and improved all other parameters in chronic aqueous-deficient DED. In evaporative DED, PS normalized corneal sensitivity and improved TBUT and fluorescein staining (osmolality and STT were not significantly changed in this model). In the desiccative stress model, PS improved TBUT and fluorescein staining but had no effect on STT or tear osmolality. PS rapidly reversed almost all DED parameters in its three subtypes. The normalization of the suppressed corneal sensitivity suggests the possibility of marked symptomatic relief by PS. The hydrogel formulation allows once-daily dosing. PS merits further development as a potential treatment for DED.
Topics: Animals; Anti-Inflammatory Agents; Delayed-Action Preparations; Disease Models, Animal; Dry Eye Syndromes; Hydrogels; Lacrimal Apparatus; Organophosphorus Compounds; Osmolar Concentration; Rabbits; Sulindac; Tears
PubMed: 34964663
DOI: 10.1089/jop.2021.0050 -
Biochimica Et Biophysica Acta.... Apr 2022Non-alcoholic steatohepatitis (NASH) is a clinically important spectrum of non-alcoholic fatty liver disease (NAFLD) in humans. NASH is a stage of NAFLD progression...
Non-alcoholic steatohepatitis (NASH) is a clinically important spectrum of non-alcoholic fatty liver disease (NAFLD) in humans. NASH is a stage of NAFLD progression wherein liver steatosis accompanies inflammation and pro-fibrotic events. Presently, there are no approved drugs for NASH, which has become a leading cause of liver transplant worldwide. To discover novel drug targets for NASH, we analyzed a human transcriptomic NASH dataset and found Aldo-keto reductase family 1 member B10 (AKR1B10) as a significantly upregulated gene in livers of human NASH patients. Similarly murine Akr1b10 and Aldo-keto reductase family 1 member B8 (Akr1b8) gene, which is a murine ortholog of human AKR1B10, were also found to be upregulated in a mouse model of diet-induced NASH. Furthermore, pharmacological inhibitors of AKR1B10 significantly reduced the pathological features of NASH such as steatosis, inflammation and fibrosis in mouse. In addition, genetic silencing of both mouse Akr1b10 and Akr1b8 significantly reduced the expression of proinflammatory cytokines from hepatocytes. These results, thus, underscore the involvement of murine AKR1B10 and AKR1B8 in the pathogenesis of murine NASH and raise an intriguing possibility of a similar role of AKR1B10 in human NASH.
Topics: Alcohol Oxidoreductases; Aldo-Keto Reductases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Cytokines; Disease Models, Animal; Hepatocytes; Humans; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; RNA Interference; RNA, Small Interfering; Sulindac
PubMed: 34954342
DOI: 10.1016/j.bbadis.2021.166319 -
Biomedicine & Pharmacotherapy =... Jan 2022Store-operated Ca channel (SOC)-regulated Ca entry is involved in inflammation and colorectal cancer (CRC) progression, but clinically applicable treatments targeting...
Store-operated Ca channel (SOC)-regulated Ca entry is involved in inflammation and colorectal cancer (CRC) progression, but clinically applicable treatments targeting this mechanism are lacking. Recent studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) not only inhibit inflammation but they also suppress Ca entry via SOC (SOCE). Therefore, delineating the mechanisms of SOCE inhibition by NSAIDs may lead to new CRC treatments. In this study, we tested eight candidate NSAIDs in Ca imaging experiments and found that Aspirin and Sulindac were the most effective at suppressing SOCE. Furthermore, time-lapse FRET imaging using TIRF microscopy and ground state depletion (GSD) super-resolution (SR) imaging revealed that SOC was inhibited by Aspirin and Sulindac via different mechanisms. Aspirin quickly interrupted the STIM1-Orai1 interaction, whereas Sulindac mainly suppressed STIM1 translocation. Additionally, Aspirin and Sulindac both inhibited metastasis-related endpoints in CRC cells. Both drugs were used throughout the study at doses that suppressed CRC cell migration and invasion without altering cell survival. This is the first study to reveal the differential inhibitory mechanisms of Aspirin and Sulindac on SOC activity. Thus, our results shed new light on the therapeutic potential of Aspirin for CRC and SOCE-related diseases.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Caco-2 Cells; Calcium Channel Blockers; Calcium Channels; Calcium Signaling; Cell Movement; Colorectal Neoplasms; Humans; Intracellular Calcium-Sensing Proteins; Membrane Proteins; Neoplasm Metastasis; Prodrugs; Sulindac
PubMed: 34864310
DOI: 10.1016/j.biopha.2021.112476