scholarly journals Withaferin A ameliorates ovarian cancer-induced cachexia and proinflammatory signaling

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Alex R. Straughn ◽  
Sham S. Kakar
Keyword(s):  
Ovarian Cancer ◽  
Skeletal Muscle ◽  
Grip Strength ◽  
Cell Line ◽  
Cancer Patients ◽  
Proinflammatory Cytokines ◽  
Xenograft Model ◽  
Withaferin A ◽  
Therapeutic Dosage ◽  
Vehicle Treatment

Abstract Background Ovarian cancer is the fifth leading cause of cancer-related deaths amongst women in the United States. Cachexia is the primary cause of death in approximately 30% of cancer patients, and is often evidenced in ovarian cancer patients. We tested the steroidal lactone Withaferin A to examine if it could ameliorate ovarian cancer-induced cachexia. Methods Six-week-old severely immunodeficient female mice were xenografted with the ovarian cancer cell line A2780 followed by treatment with Withaferin A or vehicle. Changes in functional grip strength were assessed on a weekly basis. Postmortem, H&E staining was performed on skeletal muscle sections and immunofluorescent immunohistochemistry was performed on skeletal muscle and tumor sections. The levels of NF-κB-related proinflammatory cytokines were assessed in the xenografted tumors and in resident host skeletal muscle. Results Xenografting of the A2780 cell line resulted in a significant rate of mortality, which was attenuated by a therapeutic dosage of Withaferin A. Mice that received vehicle treatment following xenografting exhibited functional muscle decline over the course of the study. The therapeutic dosage Withaferin A treatment attenuated this reduction in grip strength, whereas the supratherapeutic dosage of Withaferin A was found to be toxic/lethal and demonstrated a further decline in functional muscle strength and an increased rate of mortality on par with vehicle treatment. At a histological level, the vehicle treated tumor-bearing mice exhibited a profound reduction in myofibrillar cross-sectional area compared to the vehicle treated tumor-free control group. The atrophic changes induced by the xenografted tumor were significantly ameliorated by treatment with Withaferin A. The combination of functional muscle weakening and induction of myofibrillar atrophy corroborate a cachectic phenotype, which was functionally rescued by Withaferin A. Further, treatment completely abolished the slow-to-fast myofiber type conversion observed in the settings of cancer-induced cachexia. In both host resident skeletal muscle and the xenografted tumors, we report an increase in NF-κB-related proinflammatory cytokines that was reversed by Withaferin A treatment. Finally, we demonstrated that Withaferin A significantly downregulates cytosolic and nuclear levels of phospho-p65, the active canonical NF-κB transcription factor, in xenografted tumors. Conclusions Cumulatively, our results demonstrate a previously overlooked role of Withaferin A in a xenograft model of ovarian cancer. We propose mechanisms by which Withaferin A reduces NF-κB-dependent pro-inflammatory cytokine production leading to an attenuation of the cachectic phenotype in an i.p. xenograft model of ovarian cancer.

scholarly journals A novel targeted co-delivery nanosystem for enhanced ovarian cancer treatment via multidrug resistance reversion and mTOR-mediated signaling pathway

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xueqin Wang ◽  
Tiandi Xiong ◽  
Miao Cui ◽  
Na Li ◽  
Qin Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Multidrug Resistance ◽  
Cancer Patients ◽  
Mesoporous Silica Nanoparticles ◽  
Xenograft Model ◽  
Cell Uptake ◽  
Effective Strategies ◽  
Functionalized Mesoporous Silica ◽  
Main Challenge ◽  
Stable Combination

Abstract Background Multidrug resistance (MDR) is the main challenge of successful chemotherapy for ovarian cancer patients, with 50% to 75% of ovarian cancer patients eventually relapsed due to it. One of the effective strategies for treating MDR and improving therapeutic efficiency of ovarian cancer is to use nanotechnology-based targeted drug delivery systems. In this study, a novel nano targeted co-delivery system modified by hyaluronic acid (HA) was developed by using gold nanorods coated with functionalized mesoporous silica nanoparticles (HA-PTX/let-7a-GNR@MSN) for combined delivery of hydrophobic chemotherapy drug Paclitaxel (PTX) and lethal-7a (let-7a), a microRNA (miR), to overcome MDR in ovarian cancer. Furthermore, we also analyzed the molecular mechanism of this nanotherapeutic system in the treatment of ovarian cancer. Results HA-modified nanocomplexes can specifically bind to the CD44 receptor, which is highly expressed in SKOV3/SKOV3TR cells, achieving effective cell uptake and 150% enhancement of tumor site permeability. The nanosystem realized the stable combination and protective transportation of PTX and miRs. Analysis of drug-resistant SKOV3TR cells and an SKOV3TR xenograft model in BALB/c-nude mice showed significant downregulation of P-glycoprotein in heterogeneous tumor sites, PTX release, and subsequent induction of apoptosis. More importantly, this nanosystem could synergistically inhibit the growth of ovarian tumors. Further studies suggest that mTOR-mediated signaling pathways play an important role in reversing drug resistance and inducing apoptosis. Conclusions To sum up, these data provide a model for overcoming PTX resistance in ovarian cancer. Graphical Abstract

scholarly journals Sarcopenic Factors May Have No Impact on Outcomes in Ovarian Cancer Patients

Diagnostics ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 206 ◽  
Author(s):  
Naomi Nakayama ◽  
Kentaro Nakayama ◽  
Kohei Nakamura ◽  
Sultana Razia ◽  
Satoru Kyo
Keyword(s):  
Ovarian Cancer ◽  
Skeletal Muscle ◽  
Cancer Patients ◽  
Disease Free Survival ◽  
Muscle Volume ◽  
Muscle Quality ◽  
Prognostic Impact ◽  
Poor Prognostic Factor ◽  
Skeletal Muscle Index ◽  
The Impact

Although the prognostic value of sarcopenic factors, such as loss of muscle mass and quality, have been widely reported in patients with cancer during the last decade, the value in those with ovarian cancer remains unclear. Therefore, this study evaluated the prognostic impact of sarcopenic factors in patients with ovarian cancer. We retrospectively evaluated the data of 94 ovarian cancer patients who underwent surgery and chemotherapy at the Shimane University Hospital between March 2006 and 2013. Preoperative computed tomography scan at the level of the third lumbar vertebra was used to evaluate skeletal muscle volume and quality based on the skeletal muscle index (SMI) and intramuscular adipose tissue content (IMAC), respectively. The impact of preoperative SMI and IMAC on outcomes was subsequently investigated. Low SMI and high IMAC were not significantly associated with disease-free survival (p = 0.329 and p = 0.3370, respectively) or poor overall survival (p = 0.921 and p = 0.988, respectively). Neither preoperative low muscle volume nor low muscle quality was a poor prognostic factor in ovarian cancer.

scholarly journals Results of a phase II clinical trial of 6-mercaptopurine (6MP) and methotrexate in patients with BRCA-defective tumours

2019 ◽  
Vol 122 (4) ◽  
pp. 483-490 ◽  
Author(s):  
Corran Roberts ◽  
Victoria Y. Strauss ◽  
Sylwia Kopijasz ◽  
Charlie Gourley ◽  
Marcia Hall ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Phase Ii ◽  
Clinical Benefit ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Acquired Resistance ◽  
Xenograft Model ◽  
Progression Free Survival ◽  
Breast Cancer Patients

Abstract Background Tumour cells with BRCA1/2 gene mutations demonstrate increased sensitivity to platinum and poly (ADP-ribose) polymerase (PARP) inhibitors. 6-mercaptopurine (6MP) was found to selectively kill BRCA-defective cells in a xenograft model as effectively as the PARP inhibitor AG014699, even after these cells acquired resistance to a PARP inhibitor or cisplatin. Methods This phase II single-arm trial investigated the activity of 6MP 55–75 mg/m2 per day, and methotrexate 15–20 mg/m2 per week in advanced breast or platinum-resistant ovarian cancer patients with a BRCA1/2 germline mutation, who had progressed after ≥1 previous line of chemotherapy. The primary outcome was objective response including stable disease (SD) as an assessment of clinical benefit rate (CBR), at 8 weeks, by RECIST v1.1. Secondary outcomes included overall survival (OS) and progression-free survival (PFS). Results In total, 67 evaluable patients were recruited; 55 ovarian and 11 breast cancer patients. In total, 21 patients had SD (31%), one had a partial response (1.5%); CBR was 33% at 8 weeks. In total, 12/67 patients (18%) had SD at 16 weeks. In total, five ovarian cancer patients had SD for over 200 days. Median OS was 10.3 months (95% CI 6.9–14.5), median PFS 1.9 months (1.7–2.8). Conclusions The overall activity of 6MP and methotrexate in these patients was low; however, there was a small group of patients who appeared to derive longer-term clinical benefit. Trial registration NCT01432145 http://www.ClinicalTrials.gov.

scholarly journals Interaction of ERα and NRF2 Impacts Survival in Ovarian Cancer Patients

2018 ◽  
Vol 20 (1) ◽  
pp. 112 ◽  
Author(s):  
Bastian Czogalla ◽  
Maja Kahaly ◽  
Doris Mayr ◽  
Elisa Schmoeckel ◽  
Beate Niesler ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Mrna Expression ◽  
Cell Line ◽  
Cancer Patients ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Low Grade ◽  
Nrf2 Expression

Nuclear factor erythroid 2-related factor 2 (NRF2) regulates cytoprotective antioxidant processes. In this study, the prognostic potential of NRF2 and its interactions with the estrogen receptor α (ERα) in ovarian cancer cells was investigated. NRF2 and ERα protein expression in ovarian cancer tissue was analyzed as well as mRNA expression of NRF2 (NFE2L2) and ERα (ESR1) in four ovarian cancer and one benign cell line. NFE2L2 silencing was carried out to evaluate a potential interplay between NRF2 and ERα. Cytoplasmic NRF2 expression as inactive form had significantly higher expression in patients with low-grade histology (p = 0.03). In the serous cancer subtype, high cytoplasmic NRF2 expression (overall survival (OS), median 50.6 vs. 29.3 months; p = 0.04) and high ERα expression (OS, median 74.5 vs. 27.1 months; p = 0.002) was associated with longer overall survival as well as combined expression of both inactive cytoplasmic NRF2 and ERα in the whole cohort (median 74.5 vs. 37.7 months; p = 0.04). Cytoplasmic NRF2 expression showed a positive correlation with ERα expression (p = 0.004). NFE2L2 was found to be highly expressed in the ovarian cancer cell lines OVCAR3, UWB1.289, and TOV112D. Compared with the benign cell line HOSEpiC, ESR1 expression was reduced in all ovary cancer cell lines (all p < 0.001). Silencing of NFE2L2 induced a higher mRNA expression of ESR1 in the NFE2L2 downregulated cancer cell lines OVCAR3 (p = 0.003) and ES2 (p < 0.001), confirming genetic interactions of NRF2 and ERα. In this study, both inactive cytoplasmic NRF2 and high ERα expression were demonstrated to be associated with improved survival in ovarian cancer patients. Further understanding of interactions within the estradiol–ERα–NRF2 pathway could better predict the impact of endocrine therapy in ovarian cancer.

scholarly journals Paclitaxel Resistance in Ovarian Cancers Relies on a PGAM1 Mediated Glycolytic Metabolism

2020 ◽  
Author(s):  
Yan Feng ◽  
Xu Zhang ◽  
Songfa Zhang ◽  
Shanshan Xu ◽  
Xiaojing Chen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Line ◽  
Cancer Patients ◽  
Cancer Cell ◽  
Acid Production ◽  
Ovarian Cancer Cell ◽  
Ovarian Cancer Cell Line ◽  
Parental Cell Line ◽  
Paclitaxel Resistance ◽  
Skov3 Cells

Abstract Background: Paclitaxel, as an anti-microtubule drug, has been recommended to be the first-line chemotherapy agent for ovarian cancer for about two decades. However, most patients with advanced stage relapse within two years and ultimately die of relapsed cancer displaying increased chemoresistance. The mechanisms underlying paclitaxel resistance remain ncompletely understood.Methods: The paclitaxel-resistant ovarian cancer cell line SKOV3-TR30 and its parental cell line SKOV3 were analyzed by proteinomics. The glycolytic enzyme PGAM1-modulated glycolytic flux including pyruvic acid production and lactic acid production, and mitochondrial function was investigated using the assays kit. The correlations between PGAM1 expression, overall survival and progression free survival were evaluated for ovarian cancer patients. To elucidate the underlying mechanisms involved in paclitaxel resistance, PGAM1 gene knockout, gene overexpression and/or manipulation of glycolytic products were employed, followed by Western blot, immunostaining, and cell viability assay.Results: PGAM1 was highly expressed in the paclitaxel resistant ovarian cancer cell line SKOV3-TR30, as compared to its parental cell line SKOV3. A high expression of PGAM1 was ignificantly correlated with a reduced overall survival and progression free survival in ovarian cancer patients. Under paclitaxel exposure, SKOV3 cells showed a stronger mitochondrial function than SKOV3-TR30 cells, suggesting that under the stress, SKOV3-TR30 cells had responded with enhanced glycolysis rather than undergoing oxidative phosphorylation. Down-regulation of PGAM1 in SKOV3 TR30 cells resulted in decreased paclitaxel resistance. Up-regulation of PGAM1 in SKOV3 cells led to enhanced paclitaxel resistance. Analysis of the lycolytic flux revealed that PGAM1-mediated pyruvic acid or lactic acid production could control the capabilities of ovarian cancer cell resistance to paclitaxel.Conclusions: Our study demonstrated that PGAM1 could act as a modulator linked to paclitaxel sensitivity in ovarian cancer cells. Blocking PGAM1 may provide a new approach to reverse paclitaxel resistance in ovarian cancer patients.

scholarly journals Loss of skeletal muscle during neoadjuvant chemotherapy is related to decreased survival in ovarian cancer patients

2016 ◽  
Vol 7 (4) ◽  
pp. 458-466 ◽  
Author(s):  
Iris J.G. Rutten ◽  
David P.J. van Dijk ◽  
Roy F.P.M. Kruitwagen ◽  
Regina G.H. Beets-Tan ◽  
Steven W.M. Olde Damink ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Skeletal Muscle ◽  
Neoadjuvant Chemotherapy ◽  
Cancer Patients

Sarcopenia in Ovarian Cancer Patients, Oncologic Outcomes Revealing the Importance of Clinical Nutrition: Review of Literature

2019 ◽  
Vol 25 (22) ◽  
pp. 2480-2490 ◽  
Author(s):  
Stefano Cianci ◽  
Valerio Rumolo ◽  
Andrea Rosati ◽  
Giuseppe Scaletta ◽  
Salvatore Gueli Alletti ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Skeletal Muscle ◽  
Cancer Patients ◽  
Metastatic Breast ◽  
Muscle Quality ◽  
Oncologic Outcomes ◽  
Current Evidence ◽  
Control Series ◽  
Oncological Outcomes ◽  
The Relationship

Introduction:Ovarian cancer is the leading cause of death among gynecological malignancies. Its usual clinical manifestation is at advanced stages, with nutritional impairment, weight loss, and a consequent decline in skeletal muscle mass and strength (defined as sarcopenia). The relationship between sarcopenia and decreased survival was demonstrated not only in ovarian cancer but also in other cancer types, such as hepatocellular, pancreatic, lung, colon, cervical, metastatic breast, and renal cancer. The aim of this study is to review the current evidence regarding the relationship between sarcopenia and the surgical and oncological outcomes in ovarian cancer patients.Methods:The systematic search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRSIMA) statement. The terms “SARCOPENIA” AND “OVARIAN CANCER” were systematically used to search PubMed and Scopus databases. Original reports in English language were identified, with the purpose to include all relevant papers regarding the role of sarcopenia and indicators of skeletal muscle quality assessment in gynecological ovarian cancer.Results:A total of 9 studies were considered eligible for the present review. The strength of recommendation was moderate and the level of evidence was low in all selected articles. No prospective studies were conducted and most of the papers were case-control series comparing ovarian cancer sarcopenic population vs. non sarcopenic population.Conclusion:Sarcopenia appears to have an important role in oncological outcomes of ovarian cancer patients. However, sarcopenia occurrence during disease history and mechanisms underlying the possible impairment in prognosis should be better investigated. Prospective trials are awaited in order to obtain a better insight in this topic.

scholarly journals Disrupted Skeletal Muscle Mitochondrial Dynamics, Mitophagy, and Biogenesis during Cancer Cachexia: A Role for Inflammation

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Brandon N. VanderVeen ◽  
Dennis K. Fix ◽  
James A. Carson
Keyword(s):  
Skeletal Muscle ◽  
Cancer Patient ◽  
Cancer Patients ◽  
Proinflammatory Cytokines ◽  
Cancer Cachexia ◽  
Mitochondrial Dynamics ◽  
Primary Objective ◽  
Metabolic Function ◽  
Preclinical Models ◽  
Muscle Mass Loss

Chronic inflammation is a hallmark of cancer cachexia in both patients and preclinical models. Cachexia is prevalent in roughly 80% of cancer patients and accounts for up to 20% of all cancer-related deaths. Proinflammatory cytokines IL-6, TNF-α, and TGF-βhave been widely examined for their regulation of cancer cachexia. An established characteristic of cachectic skeletal muscle is a disrupted capacity for oxidative metabolism, which is thought to contribute to cancer patient fatigue, diminished metabolic function, and muscle mass loss. This review’s primary objective is to highlight emerging evidence linking cancer-induced inflammation to the dysfunctional regulation of mitochondrial dynamics, mitophagy, and biogenesis in cachectic muscle. The potential for either muscle inactivity or exercise to alter mitochondrial dysfunction during cancer cachexia will also be discussed.

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