Chemoprotective Effects Research Articles

Fish Oil's Preventive Effect on Two-Stage Skin Carcinogenesis in Swiss Albino Mice: Involvement of NF-ҝB Pathways and Oxidative Stress in a Dose- and Route Dependent Manner.

This study investigated the chemopreventive mechanisms of fish oil (FO) at different doses and administration routes in skin carcinogenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA) and croton oil (CO) in Swiss albino mice. Seventy mice were divided into 10 groups, including controls and those receiving FO either orally or topically, with or without the carcinogenesis protocol. Warts were morphologically analyzed. Anatomopathological analysis, qRT-PCR of nuclear factor kappa B (NF-қB) subunits' gene expression, and evaluation of oxidative parameters were conducted. Anatomopathological analysis revealed a presence of invasive squamous cell carcinoma (SCC) in DMBA group. Both oral (500mg/kg/day) and topical FO treatment showed no signs of cancer, while oral administration at 50mg/kg/day had no therapeutic effect, and 250mg/kg/day resulted in low-grade malignancy. Both oral (250 and 500mg/kg/day) and topical FO significantly reduced NF-кB1 gene expression, alleviated oxidative stress markers, and restored antioxidant enzyme activities compared to the DMBA group. FO shows dose-dependent chemopreventive effects, with oral administration potentially as effective as topical application when using an appropriate dosage. The development of SCC is linked to the stress status and the upregulation of the canonical NF-κB pathway, while FO's chemoprotective effects likely result from its downregulation.

Chemoprotective Effect of Myrrhone against Diethylnitrosamine and Ferric Nitrile Induced Renal Cancer via Alteration of HO-1/Nrf2 and TRL4/NF-κB Signaling Pathway.

. Following a single dose of intraperitoneal DEN (200 mg/kg) and a twice-weekly administration of Fe-NTA, rats were administered either an oral dose of myrrhone (5, 10, or 15 mg/kg). The body weights and food intake of the rats were monitored at regular intervals, and the levels of renal cancer markers, antioxidants, inflammatory markers, and other parameters were assessed. Additionally, histopathological studies were conducted on the renal tissues, and the mRNA expression of Bax, Bcl-2, HO-1, SOD2, mtDNA, ATP8, PGC-1α, TRL4, and NF-κB was analyzed. . The dosage-dependent administration of myrrhone demonstrated a remarkable suppression of tumor incidence and an improvement in body weight and food intake. Myrrhone markedly decreased the level of ODC, Thymidine [3H] incorporation, and renal parameters such as creatinine, uric acid, BUN, Kim-1, Cysc-C, and LDH. Additionally, myrrhone significantly altered the levels of MDA, GSH, GPx, CAT, and SOD, as well as inflammatory cytokines such as TNF-α, INF-γ, IL-1β, IL-6, and IL-10, and inflammatory parameters such as COX-2, PGE2, TGF-β1, NF-κB, and iNOS. Furthermore, myrrhone significantly decreased the histopathological score and improved the condition of histopathology. Finally, myrrhone significantly altered the mRNA expression of Bax, Bcl-2, HO-1, SOD2, mtDNA, ATP8, PGC-1α, TRL4, and NF-κB. : The result clearly showed the chemoprotective effect of myrrhone against diethylnitrosamine and ferric nitrile induced Renal Cancer via alteration of HO-1/Nrf2 and TRL4/NF-κB Signaling pathway.

Long-term use of low-dose aspirin for cancer prevention: A 20-year longitudinal cohort study of 1,506,525 Hong Kong residents.

Long-term use of low-dose aspirin has been demonstrated to reduce cancer risk, but the duration of necessary medication use remains uncertain. This study aimed to investigate the long-term chemoprotective effect of aspirin among the Chinese population. This population-based study included all aspirin users between 2000 and 2019. Aspirin users were age-sex matched with non-users at a 1:2 ratio. Cancer incidence and mortality were the main outcomes measured. Survival analyses with the Fine-Gray modelling were performed. The chemoprotective effects were measured by the sub-distribution hazard ratios (SHR) with control for the competing risks. A total of 538,147 aspirin users and 968,378 non-users were included, with a mean age of 64.8 years, 9,543,399 person-years of follow-up and 90% of users with 80 mg aspirin. The long-term use of aspirin was associated with a reduced risk of cancer (SHR 0.92, 95% CI 0.91-0.94) and a reduced risk of cancer mortality (SHR 0.80, 95% CI 0.79-0.82). Stronger chemopreventive effects were observed among those who used aspirin for more than 10 years, including risk reductions for lung (SHR 0.56, 95% CI 0.51-0.60), breast (SHR 0.34, 95% CI 0.29-0.38) and colorectal (SHR 0.37, 95% CI 0.33-0.40) cancers, but not for bladder cancer and leukaemia. Low-dose use of aspirin was associated with lower risk of cancer among Chinese. The association was even stronger for those using aspirin for more than 10 years. Prescription of aspirin may be started as early as at age of 40, as the chemoprotective effect also applied for early cancers.

Exploring the Anticancer Potential of MonoHER (7-Mono-O-(β-Hydroxyethyl)-Rutoside): Mitochondrial-Dependent Apoptosis in HepG2 Cells.

Flavonoids are a group of polyphenols, abundantly present in our diet. Although, based on their chemoprotective effects, intake of flavonoids is associated with a high anticancer potential as evidenced in in vitro and in vivo models, the molecular mechanism is still elusive. This study explores the antiproliferative and cytotoxic effects of the semi-synthetic flavonoid MonoHER (7-mono-O-(β-hydroxyethyl)-rutoside) in vitro on cancer cells. HepG2 liver, MCF7 breast, and H1299 lung cancer cells were grown under ambient conditions with or without MonoHER exposure. CCK8 assay was used to assess cell viability. Apoptosis, JC-1, and mitochondrial mass were determined using flow cytometry and confocal analysis. The effects of monoHER on apoptosis proteins were detected by confocal microscopy analysis and Western blot. It was found that MonoHER can reduce HepG2 cells' and MCF7 cells' viability, but not H1299 cells', and induced apoptosis only in HepG2 cells. MonoHER has the potential to enhance the expression of caspase-9 and caspase-3, to damage mitochondria, and to provoke the release of cytochrome C from the mitochondria. MonoHER can inhibit cell growth and induce apoptosis especially in HepG2 human liver cancer cells by triggering the mitochondrial signal transduction pathway, leading to the release of cytochrome C in the cytoplasm and the subsequent activation of caspase-9 and caspase-3. Future research should further explore MonoHER's mechanism of action, efficacy, and potential for clinical translation.

Evaluating the Role of Aspirin in Liver Disease: Efficacy, Safety, Potential Benefits and Risks.

The rise in liver disease incidence and prevalence has led to increasing morbidity and mortality worldwide. Persistent hepatic inflammation drives disease progression by increasing fibrosis, advancing to cirrhosis, and potentially developing into hepatocellular carcinoma (HCC). Addressing these complications is essential to reduce liver-related mortality. Recent studies suggest that non-steroidal anti-inflammatory drugs, particularly aspirin, may play a beneficial role in managing liver disease. Aspirin's anti-inflammatory and chemoprotective effects contribute to slowing disease progression and reducing the risks associated with chronic liver disease (CLD). This review highlights the current literature on the effects of aspirin in CLD, with a focus on patients with metabolic-associated steatotic liver disease (MASLD) and hepatitis B and C. We will examine aspirin's potential ability to mitigate fibrosis, reduce the incidence of HCC, and lower liver-related mortality. Additionally, we will discuss its potential side effects and safety considerations, particularly in the context of liver disease, where there is an increased risk of bleeding.

Preparation of gallic acid-loaded chitosan nanoparticles and their chemoprotective effects on N-ethyl-N-nitrosourea-induced hepatotoxicity and mortality in rats.

N-ethyl-N-nitrosourea (ENU) as n-nitrosamine and alkylating agent, ubiquitous within living cells and in the environment can act as a full carcinogen and induce tumor formation in various tissues such as liver. In this study, gallic acid-loaded chitosan nanoparticles (GANPs) were synthesized and evaluated for their chemopreventive effect against ENU-induced hepatotoxicity and mortality in rats. Twenty-four male Wistar rats were divided into four groups including: control, ENU (single doses of 50mg/kg via intraperitoneal injection), GA + ENU and GANPs + ENU. Animals were orally pretreated with GA (50 mg/kg) and GANPs (50 mg/kg) for 30 days, and liver injuries induced by ENU on the 31st day of study. After ENU administration, weight changes and mortality were monitored during 30 days, and then the animals were sacrificed and alpha-fetoprotein (AFP) as a tumor marker, liver function tests (ALT, AST and ALP), oxidative stress markers (GSH and MDA), mitochondrial toxicity parameters, and histopathological assessment were evaluated. Except for AFP and MDA, ENU caused significant elevation of liver enzymes, mitochondrial ROS formation, collapse of mitochondrial membrane potential depletion of GSH, histopathological abnormalities and mortality in rats. Our data showed that GANPs significantly increased the survival of rats by up to 66%, delayed in death time and prevented weight changes after exposure to ENU. Moreover, GANPs restored liver enzyme levels, ROS formation, mitochondrial dysfunction, GSH levels, and histopathological abnormalities towards normal. Our findings suggest that GANPs revealed a significant protective effect against deadly toxicity induced by ENU as an alkylating full carcinogen agent in liver tissue.

Neutrophil extracellular traps promote tumor chemoresistance to anthracyclines.

The microenvironment plays an important role in promoting tumor cell chemoresistance, but the mechanisms responsible for this effect are not clear. Here, using models of multiple myeloma (MM) and solid cancers, we demonstrate a novel mechanism mediated by neutrophils, a major cell population in the bone marrow (BM), that protects cancer cells from chemotherapeutics. We show that in response to tumor-derived soluble factors, BM neutrophils release their DNA in the form of neutrophil extracellular traps (NETs). Cell-free DNA derived from NETs is then taken up by tumor cells via endocytosis and localizes to the cytoplasm. We found that both NETs and cell-free DNA taken up by tumor cells can bind anthracyclines, leading to tumor cell resistance to this class of chemotherapeutic agents. Targeting cell-free DNA with Pulmozyme or blocking NET formation with a PAD4 inhibitor abrogates the chemoprotective effect of neutrophils and restores sensitivity of tumor cells to anthracyclines.

Chemoprotective Effect of Bryodulcosigenin against 7,12-Dimethylbenz(a)anthracene-induced Breast Cancer via Suppression of Inflammation, Oxidative Stress, and Apoptosis

Chemoprotective Effect of Bryodulcosigenin against 7,12-Dimethylbenz(a)anthracene-induced Breast Cancer via Suppression of Inflammation, Oxidative Stress, and Apoptosis

The chemoprotective hormetic effects of rosmarinic acid.

Rosmarinic acid is a polyphenol found in numerous fruits and vegetables, consumed in supplement form, and tested in numerous clinical trials for therapeutic applications due to its putative chemopreventive properties. Rosmarinic acid has been extensively studied at the cellular, whole animal, and molecular mechanism levels, presenting a complex array of multi-system biological effects. Rosmarinic acid-induced hormetic dose responses are widespread, occurring in numerous biological models and cell types for a broad range of endpoints. Consequently, this article provides the first assessment of rosmarinic acid-induced hormetic concentration/dose responses, their quantitative features, mechanistic foundations, extrapolative strengths/limitations, and their biomedical, clinical, and public health implications.

Chemoprotective Effect of Eugenol on Repeated dose Doxorubicin, Induced Genotoxic Lesions in Mouse Bone Marrow

In present study, an attempt has been made to evaluate the possible in vivo chemoprotective potential of eugenol against doxorubicin induced genotoxic lesion in bone marrow. Swiss albino female mice were administered Eugenol (10 mg/kg/day, orally) 15 days before doxorubicin administration as well as concomitantly with doxorubicin. Genotoxic lesions were induced by a repeated dose intraperitoneal injection of doxorubicin (5mg/kg b.w. i.p. upto 9 days (alternate day). Micronuclei assay and COMET assay were carried out to determine genetic damage in bone marrow. Histopathological evaluation of bone marrow was also done to study lesions at cellular level. The study results demonstrated that eugenol significantly mitigated Doxorubicin induced micronuclei formation and DNA damage in the bone marrow niche. Histopathological observations revealed that Doxorubicn-intoxication resulted in massive structural impairment of bone marrow which was reduced by eugenol administration. Amelioration by eugenol is more significant in mice those received eugenol 15 days prior to Doxorubicin administration suggesting its chemoprotection. The present study suggests eugenol has the promising chemoprotective effect against Doxorubin-induced genetic lesions in mice bone marrow.

Anti-tumor property of Argemone mexicana leaves methanol extracts against 7, 12- Dimethylbenz[a]anthracene (DMBA) induced mammary tumors in experimental rats

Background: Breast cancer is a complex and multistage process. Many natural compounds are available for an effective and efficient alternative method against breast cancer. This study focused on the anti-cancer activity of Argemone mexicana leaf extract on Dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in experimental rats. Materials and Methods: Argemone mexicana Leaves (AML) were collected, extracted by soxhlet apparatus with methanol solvent, and analyzed by Gas Chromatography and Mass-Spectroscopy (GCMS). Healthy Female Sprague-Dawley rats (7-8 weeks and 100 ± 20 g) were divided in five groups and used to induce mammary tumors by DMBA [25 mg/kg/ Subcutaneous (s.c.)]. After developing a palpable nodule (10-12 weeks after DMBA), the rats were treated with AML extract [200 and 400 mg/kg/Body Weight (b.w.)] and Tamoxifen (TAM 10 mg/kg) orally for 12 weeks. Body weight, tumor weight and volume measurements, lipid peroxidation, antioxidant and tumor marker [Carcinoembryonic Antigen (CEA)] levels, and histological investigations were assessed. Results: Following AML treatment, there was a reduction in weight and volume (P< 0.01) of breast tumor, as well as a significant decrease in levels of lipid peroxidation and tumor marker CEA (P < 0.001) and improved Superoxide Dismutase (SOD), Reduced glutathione (GSH), and caspase levels (P < 0.001). In cytological results, AML improved the cellular architecture, and significant restoration in histopathological examinations revealed a tumor with minimal glandular epithelium proliferation, a decrease in mitotic figures, and nuclear alterations. Conclusion: The study suggests that AML extract has a chemoprotective effect against DMBA-induced mammary tumors in experimental animals, specifying its possibility as a therapeutic agent for breast cancer treatment.

Tadalafil pretreatment attenuates doxorubicin-induced hepatorenal toxicity by modulating oxidative stress and inflammation in Wistar rats

Doxorubicin (DOX) is a widely used anticancer agent, but its clinical application is limited by significant off-target hepatorenal toxicity. Tadalafil (TAD), a selective phosphodiesterase-5 inhibitor used mainly for erectile dysfunction and pulmonary arterial hypertension, has shown potential in reducing oxidative stress. This study investigated TAD's chemoprotective effects and underlying mechanisms in DOX-induced hepatorenal toxicity in rats over 12 days. Eight groups of six rats each were orally pretreated with sterile water, silymarin (SIL), or TAD one hour before receiving intraperitoneal injections of 2.5 mg/kg DOX. On the 13th day, the rats were humanely sacrificed under inhaled halothane anesthesia, and serum was collected for hepatic and renal function tests, while liver and kidney tissues were analyzed for antioxidant enzyme activity, pro-inflammatory cytokines assay, and histopathological evaluation. DOX successfully induced hepatorenal toxicity, evidenced by significant increases (p<0.001, p<0.0001) in serum K+, urea, and creatinine levels, along with decreases in HCO3-, TCa2+, and Cl-. Tissue analysis showed reduced SOD, CAT, GST, and GPx activities, with elevated MDA and GSH levels. TAD pretreatment significantly ameliorated these biochemical alterations (p<0.05, p<0.001, p<0.0001), suggesting its potential as an effective chemoprophylactic adjuvant in the development of DOX-induced hepatorenal toxicity.

Characterization of Extractable and Non-Extractable Phenols and Betalains in Berrycactus (Myrtillocactus geometrizans) and Its Chemoprotective Effect in Early Stage of Colon Cancer In Vivo.

This research identified the bioactive compounds and antioxidant capacity of the extractable (EP) and non-extractable (NEP) polyphenol fractions of berrycactus (BC). Additionally, the effects of BC and its residue (BCR) on preventing AOM/DSS-induced early colon carcinogenesis were evaluated in vivo. Male Sprague Dawley rats were randomly assigned to six groups (n = 12/group): healthy control (C), AOM/DSS, BC, BCR, BC+AOM/DSS, and BCR+AOM/DSS. NEP was obtained through acid hydrolysis using H2SO4 and HCl (1 M or 4 M). The HCl-NEP fraction exhibited the highest total phenolic and flavonoid content, while condensed tannins were more abundant in the H2SO4-NEP fraction. A total of 33 polyphenols were identified by UPLC-QTOF-MSE in both EP and NEP, some of which were novel to BC. Both NEP hydrolysates demonstrated significant total antioxidant capacity (TEAC), with HCl-NEP exhibiting the highest ORAC values. The BC+AOM/DSS and BCR+AOM/DSS groups exhibited fewer aberrant crypt foci (p < 0.05), reduced colonic epithelial injury, and presented lower fecal β-glucuronidase activity, when compared to AOM/DSS group. No differences in butyric acid concentrations were observed between groups. This study presents novel bioactive compounds in EP and NEP from BC that contribute to chemopreventive effects in early colon carcinogenesis, while reducing fecal β-glucuronidase activity and preserving colonic mucosal integrity.

5α-reductase inhibitors with or without alpha-blockers and risk of incident upper tract urothelial carcinoma in men with benign prostatic hyperplasia: Analysis of US insurance claims data

BackgroundIncreasing data suggests that androgen receptor signaling may play an important role in the carcinogenesis of urothelial cancers. While the chemoprotective effect of 5-alpha reductase inhibitors (5-ARi) on bladder cancer risk in men with Benign Prostatic Hyperplasia (BPH) has been explored with conflicting results, the evidence regarding 5-ARi treatment, and the risk of incident Upper Tract Urothelial Carcinoma (UTUC) development is lacking. Therefore, our objective was to investigate the impact of the 5-ARi administration on the incidence of new UTUC cases using a large US database. MethodsThe MerativeTM Marketscan® database was used to identify men ≥ 50 years old with a diagnosis of BPH and an active 5-ARi prescription between 2007 and 2021 and were subsequently matched with paired controls. A multivariable Cox regression model was implemented to ascertain the association of 5-ARi and/or alpha-blocker (α-B) medications on the incidence of UTUC. Additional subgroup analyses were conducted based on exposure risk (with a 2-year threshold) to investigate the relationship between 5-ARi and UTUC over time. ResultsOverall, n=1,103,743 men BPH without prescriptions for BPH, n=31,142 men on 5-ARi, and n=160,049 using 5-ARi + α-B were identified. Over the follow-up period, a total of n=4,761 patients were diagnosed with UTUC. After matching, UTUC incidence ranged from 0.36% to 0.41% in men without active BPH therapy vs. 0.30% and 0.52% for the 5-ARi and 5-ARi + α-B groups, respectively. In multivariable analysis, the chemoprotective effect on UTUC risk was not observed for either 5-ARi monotherapy (adjusted hazard ratio [aHR]: 0.91, 95% CI: 0.58–1.44) or 5-ARi + α-B combination (aHR: 1.02, 95% CI: 0.87–1.19). This remained true for both short-term (≤ 2 years) and long-term (> 2 years) follow-up periods. ConclusionsThe use of 5-ARi for BPH, whether used alone or in combination with α-B, is not associated with incident UTUC.

Protective effects of Butylated Hydroxytoluene (BHT) against sodium Arsenite (NaAsO2) - Induced hepatotoxicity in Wistar Rats

One of the major environmental contaminants that can be found on a global scale is arsenic. Sodium arsenite (NaAsO2) is one of the compounds of arsenic which is considered very toxic. Long term exposure to NaAsO2 can cause chemical complications in various organs of the body such as the liver, kidney, testes and brain tissues. Butylated hydroxytoluene (BHT) is an antioxidant that can serve as an antitoxic effect. NaAsO2. In this topic, we examined the chemo-protective effect of BHT on NaAsO2 induced hepatotoxicity in male Wistar rats. Wistar rats (n=42, +120g) were randomly grouped into seven treatment groups: of 7 animals each Control 1(corn oil); Control 2(distilled water); NaAsO2 alone (2.5mg/kg). BHT alone (25 mg/kg); BHT only (25mg/kg); BHT+ NaAsO2 (25mg/kg + 2.5/kg), and BHT+ NaAsO2 (2.5g/kg + 50 mg/kg) and treated for 14 days. Markers of liver functions, inflammation, oxidative stress and antioxidant profile of liver were assayed spectrophotometrically. Our results showed that exposure to NaAsO2 resulted in dramatic increase in the levels of AST, ALT and ALP activity Furthermore, NaAsO2 increased the concentration of oxidative stress markers such as xanthine oxidase (XO) and lipid peroxidation (MDA) and inflammatory markers such as myeloperoxidase (MPO) and nitric oxide (NO) with a concomitant decrease in antioxidant markers such as superoxide dismutase (SOD). Glutathione-S-transferase (GST), and catalase. However, the co-exposure of rats to both BHT and NaAsO2 can result in significant decrease the parameters above. In conclusion, exposure of rats to NaAsO2 causes increased inflammatory and oxidative stress signals, but these harmful effects can be ameliorated by administration of antioxidants such as BHT as confirmed by this research.

Are associations between adherence to the 2018 WCRF/AICR cancer prevention recommendations and risk of cancers modulated by multimorbidity? Findings from the UK Biobank prospective cohort study

Approximately 40% of cancers in the UK are attributable to modifiable, lifestyle risk factors such as overweight and obesity and low dietary fibre intake(1). The WCRF and AICR published ten lifestyle- based Cancer Prevention Recommendations with the aim of reducing the risk of cancer and other non-communicable diseases(2). In the UK Biobank cohort, we have found reduced risk of cancer overall and of breast and colorectal cancers with greater adherence to these Cancer Prevention Recommendations (i.e., healthier lifestyles). The present study aimed to investigate whether the magnitude of these associations is modified by the presence of co-morbidities, such as diabetes and cardiovascular disease, at baseline.We used data from 94,778 participants (53% female, mean age 56 years) from the UK Biobank prospective cohort study, recruited between 2006 and 2010 and free from cancer at baseline. Adherence to the 2018 WCRF/AICR Cancer Prevention Recommendations was calculated from dietary, physical activity, and body composition data using a standardised score(3). Multimorbidity (list of 43 chronic diseases) was self-reported at baseline and categorised into: 0, 1, 2, or 3+ chronic illnesses. Incident cancer cases were identified using population-based cancer registries available until July 2019 for England and Wales and October 2015 for Scotland. Participants were categorised into approximate score tertiles, and the lowest tertile (lowest adherence, 0-3.5 points) was used as the reference category. Cox proportional hazard models were used to investigate associations between total score and incidence of cancer, adjusting for confounders, and to test for an interaction between total score and multimorbidity.55,191 (58%) participants had one chronic illness at baseline and 8,430 (9%) had ≥3. Mean total 2018 WCRF/AICR score was 3.8 (SD 1.0) points, and participants with the presence of chronic illnesses had a significantly lower total score (mean for ≥3 illnesses = 3.58 points vs 3.96 points for participants without chronic illness, p&lt;0.001). During a median follow-up of 8 years, 3,303 individuals developed cancer. When investigating associations between score tertiles and the risk of cancer overall, there was a significant interaction between the total score and multimorbidity (HR for interaction: 1.59, p=0.002). There was also evidence for an interaction between total score and multimorbidity with breast cancer risk (HR for interaction: 1.23, p=0.030), but no evidence of an interaction between total score and multimorbidity for risk of colorectal cancer.We found stronger associations between total adherence score and the risk of cancer in participants with ≥3 chronic illnesses. This suggests that the chemoprotective effects of greater adherence to the 2018 WCRF/AICR Cancer Prevention Recommendations may be particularly beneficial for individuals with multimorbidity.

Genetic Variations Related to Angiotensin II Production and Risk for Basal Cell Carcinoma.

Basal cell carcinoma (BCC) is the most prevalent human neoplasm, with constantly increasing annual incidence. Despite its slow growth, BCC is locally invasive and, if left untreated, can cause severe complications, including metastasis and death. The renin-angiotensin system (RAS) plays a key role in electrolyte balance, atrial pressure, tissue development, homeostasis, and inflammation, but also in cancer development. After binding to its type 1 receptor (AT1R), angiotensin II (ANGII), the system's principal hormonal effector, regulates cancer pathways spanning from the formation of the initial cancer cell to the construction and nutrition of the tumor microenvironment, angiogenesis, proliferation, and metastasis. Although the role of RAS in the development of skin pathologies has not been widely researched, RAS-targeting antihypertensive medications have been shown to have a chemoprotective effect against BCC. Based on those findings, our group conducted a series of genetic association studies to investigate the association between common functional variations in key genes related to ANGII production (AGT, ACE, ACE2, AT1R, AT2R, and CMA1) and the risk of BCC occurrence. This review provides a summary of the current understanding of the ANGII involvement in BCC development. The reliable and easily assessed pool of genetic biomarkers may be used for predictive testing and prevention purposes in high-risk individuals.

Punica granatum L. (Pomegranate) Extracts and Their Effects on Healthy and Diseased Skin.

The aim of this review is to provide a summary of the botany, phytochemistry and dermatological effects of Punica granatum (PG), with special emphasis on therapeutic mechanisms in various skin conditions. PG peel contains the highest levels of chemical compounds. Due to the high abundance of polyphenolic compounds, including phenolic acids, anthocyanins and flavonoids, exhibiting strong antioxidant properties, PG peel possesses significant health-promoting effects. Up until now, different parts of PG in the form of various extracts, fixed seed oil or individual active compounds have been investigated for various effects on skin conditions in in vitro and in vivo studies, such as antioxidant, anti-inflammatory, antimicrobial, chemoprotective and antiaging effects, as well as positive effects on striae distensae, skin repair mechanisms, erythema, pigmentation and psoriasis. Therefore, formulations containing PG active compounds have been used for skincare of diseased and healthy skin. Only a few effects have been confirmed on human subjects. Based on encouraging results obtained in in vitro and animal studies about the numerous substantial dermatological effects of PG active compounds, future perspectives should incorporate more in vivo investigations in human volunteers. This approach can aid in identifying the optimal concentrations and formulations that would be most efficacious in addressing specific skin conditions.

Abstract 2019: Primary cancer associated fibroblasts increase the chemoresistance of triple negative breast cancer cells by mitochondria metabolic upregulation

Abstract Breast cancers (BCs) are the most prevalent cancers occurring in women. Tumor reoccurrence attributed to chemotherapy resistance remains a main challenge in fighting disease relapse. Cancer associated fibroblasts (CAFs) are the most prominent component of the tumor microenvironment (TME) and have already been implicated in therapy resistances. Although the exact molecular mechanisms behind this resistance remain unclear. In this regard, we recently identified 4 CAF populations (S1-S4) in ovarian and BCs, and showed that only CAF-S1 promote immunotherapy resistance as well as metastasis. Based on these observations, we are now investigating the impact of CAF-S1 on the chemotherapy response of BCs. To study the interactions between CAF-S1 and BC cells, we developed a tumor on chip (ToC) device, mimicking the TME in 3D. Using ToC live imaging, we show that primary CAF-S1 mediate a chemoprotective effect over luminal and triple negative BC (TNBC) cells by significantly decreasing their apoptosis rate as early as 10h after Doxorubicin and 40h after Paclitaxel treatment. Interestingly, CAF-S1 display a highly heterogenous response to Doxorubicin, allowing the classification into chemo-sensitive and -resistant CAF-S1. Regardless of premature CAF-S1 cell death, the chemoprotective effect over BC cells is maintained for at least 3 days. This indicates a crucial CAF-S1 - cancer cell cross talk at early timepoints. Additionally, by applying machine learning algorithms on live imaging videos, we demonstrate that physical proximity of CAF-S1 to BC cells immediately after treatment initiation correlates with BC cell survival, even after several days of treatment. This again implies cancer cell priming by CAF-S1 as a possible mechanism of chemotherapy resistance. To investigate this molecular interplay further, we performed scRNA-seq of ToC extracted and treatment naïve CAF-S1 and TNBC cells as well as bulk RNA-seq of patient derived TNBC tumors before/after chemotherapy treatment. We identify mitochondrial metabolic pathways to be upregulated in TNBC cells after CAF-S1 co-culture inside ToC devices and in TNBC cells of chemo-resistant patients enriched in CAF-S1 at baseline. We are now validating the impact of target gene knock downs on the survival of TNBC cells in CAF-S1 co-cultures after chemotherapy treatment on chip. Overall, these results provide insights into molecular mechanisms by which CAF-S1 promote chemotherapy resistance of breast cancers. Citation Format: Isabella Hofer, Arianna Mencattini, Yann Kieffer, Eugenio Martinelli, Maria Carla Parrini, Fatima Mechta-Grigoriou. Primary cancer associated fibroblasts increase the chemoresistance of triple negative breast cancer cells by mitochondria metabolic upregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2019.

Abstract A090: An inflammatory adipose microenvironment promotes ovarian cancer tumor growth and cisplatin resistance

Abstract Epithelial ovarian cancer (EOC) commonly targets the omentum, an adipocyte rich organ of the peritoneum. Omental adipocytes have been shown to promote EOC development and chemoresistance via transfer of free fatty acids (FFAs) and the induction of bi-directional metabolic changes. Furthermore, obesity and adiposity are risk factors for EOC incidence and prognosis. The metastatic peritoneal tumor microenvironment (TME) is highly inflamed, while obesity is often characterized by chronic inflammation of adipose tissue and hyperlipidemia. Given that inflammation of adipocytes is associated with increased release of FFAs, we hypothesized that acute inflammation in the ovarian metastatic TME exacerbates pro-tumorigenic effects of cancer-associated adipocytes. Using a three-dimensional transwell co-culture model, we explore the impact of inflamed adipocytes on EOC activity. Adipocytes generated from human adipose-derived stem cells were inflamed with 100ng/ml TNFα and cultured alongside tumor spheroids generated from EOC cell lines. Cytokine abundance in serum samples from ovarian cancer patients undergoing cisplatin treatment were also analyzed. We found that inflammation of adipocytes increased cellular lipolysis and release of FFAs, as well as inducing de-differentiation and loss of lipid droplets. Upon co-culture with inflamed adipocytes, EOC cells displayed increased proliferation in 2D monolayer and 3D spheroid cultures. Transfer of FFAs from adipocytes to cancer cells was visualized and quantified using a fluorescent fatty acid analog via confocal microscopy and flow cytometry. Co-culture induced expression of fatty acid chaperone protein FABP4 in EOC cell lines, while blocking fatty acid metabolism in cancer cells reversed pro-tumor effects of adipocytes. To understand signaling mechanisms generating bi-directional phenotypic changes, cytokine content of secretome of co-cultures was assessed by Luminex. IL-6 and IL-8 were highly abundant in co-cultures, and increased expression was confirmed by qPCR. Treatment of EOC cell lines with recombinant IL-6 and IL-8 induced increased uptake of FFAs and blocking of IL-6 and IL-8 signaling reversed pro-cancer effects of adipocytes. Serum samples from patients undergoing cisplatin therapy were analyzed and IL-6 and IL-8 levels were found to be associated with resistance to therapy. To further investigate the impact of inflamed adipocyte signaling on therapeutic resistance, co-culture were treated with cisplatin and tumor spheroids were found to be highly resistant in the presence of inflamed adipocytes. STAT3 activity is known to be upregulated by both IL-6 and IL-8 and we found that STAT3 expression was increased in co-cultures. Knockdown of STAT3 in EOC reversed the chemoprotective effects of inflamed adipocytes. These data suggest an important role for inflammation of adipose tissue in the development of therapeutic resistance in EOC and highlight a potential mechanism linking clinically observed associations between obesity and ovarian cancer risk. Citation Format: Michael E. Williams, David Howard, Deyarina Gonzalez, Francesca Taraballi. An inflammatory adipose microenvironment promotes ovarian cancer tumor growth and cisplatin resistance [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A090.