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 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 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.

Expression of multidrug resistance-1 protein inversely correlates with paclitaxel response and survival in ovarian cancer patients: a study in serial samples

2004 ◽  
Vol 93 (1) ◽  
pp. 98-106 ◽  
Author(s):  
Richard T Penson ◽  
Esther Oliva ◽  
Steven J Skates ◽  
Tina Glyptis ◽  
Arlan F Fuller ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Multidrug Resistance ◽  
Cancer Patients ◽  
Serial Samples

Immunoreactive score of Ep-CAM might predict survival in early ovarian cancer patients

2011 ◽  
Vol 71 (08) ◽  
Author(s):  
MJ Battista ◽  
J Steetskamp ◽  
N Mantai ◽  
S Gebhard ◽  
C Cotarelo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Early Ovarian Cancer

ROLE OF LIPID PROFILE IN OVARIAN CARCINOMA PATIENTS

2019 ◽  
Vol 3 (8) ◽  
Author(s):  
Dr. Manisha ◽  
Dr. Ruchi Jindal
Keyword(s):  
Ovarian Cancer ◽  
Lipid Profile ◽  
Cancer Patients ◽  
Ovarian Tumor ◽  
Ovarian Cancer Risk ◽  
Low Level ◽  
Medical College ◽  
Group I ◽  
History Of

Background: The term "ovarian cancer" includes several different types of cancer that  arise from cells of the ovary, most commonly, tumors arise from the epithelium or lining cells of the ovary.  Ovarian cancer risk is positively associated with higher consumption of dietary cholesterol and eggs, and inversely associated with a higher intake of vegetables. High consumption of fats may increase circulating estrogen levels, thus increasing the possibility of cell damage and proliferation that is responsible for cancerous growth. Material & Methods: The present study was conducted at Geetanjali Medical College and Hospital, Udaipur (Rajasthan). Total  100 cases (females) attending the obstetrics and gynecology department for some gynecological and other problem  were selected for this study between the age of 40-60 years, who were attending cancer centre at GEETANJALI MEDICAL COLLEGE AND  HOSPITAL, Udaipur (Rajasthan).                GROUP I: - It consisted of healthy females control subjects (n=50) .By routine examination and tests, we ensured that all the subjects were healthy and there were no signs and symptoms or history of ovarian tumor and diseases GROUP II: - It consisted of ovarian cancer females subjects (n=50) with a history of ovarian tumor. Results:   Higher level of cholesterol, LDL, VLDL and low level of HDL are found in ovarian cancer patients. Conclusion: The present study we highlights the importance and role of serum lipid profile in diagnosis, prognosis and recurrence of the disease. The study shows that serum level of cholesterol, LDL, VLDL was elevated in  patients of ovarian cancer while low level of HDL are found in ovarian cancer patients. Key words: lipid profile, ovarian cancer.

Frequency of blood transfusions for anemia due to chemotherapy in ovarian cancer patients. Thoughts to the guidelines modified in 2006 for the treatment of anemic cancer patients by the European Organisation for Research and Treatment of Cancer

2007 ◽  
Vol 148 (45) ◽  
pp. 2133-2137 ◽  
Author(s):  
Ottó Lehoczky ◽  
Tamás Pulay
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Blood Transfusions ◽  
European Organisation

2006-ban jelent meg az Európai Rákkutatási és Kezelési Szervezet korábbi megállapításokat korszerűsítő ajánlása, amelyben a rákos betegekben kialakuló anémia kezelésére adott vértranszfúziót, illetve az ezt követő erythropoetin-kezeléseket értékelik. Az ajánlásban a vértranszfúziót a 9 g% hemoglobinszintre csökkenő anémia esetén javasolják. Eddig a kemoterápia következtében kialakult anémia vértranszfúziós kezelésére egyértelműen meghatározott hemoglobin-határértékszint Magyarországon nem szerepelt. Cél: A szerzők az osztályukon 2005-ben kezelt petefészekrákos betegeknek adott vértranszfúziók gyakoriságát vizsgálták. Nemzetközi, illetve hazai egyértelmű ajánlás hiányában a vizsgálati időszakban a vértranszfúziókat – a beteg klinikai állapotát is figyelembe véve – a 10 g%-ot elérő anémia esetén alkalmazták. Anyag és módszer: Az Országos Onkológiai Intézet Nőgyógyászati Osztályán 190 hám eredetű, petefészekrákos betegben történt kemoterápia. Ha a hemoglobinszint 10 g% alá csökkent, választott vörösvértest-transzfúziót végeztek, majd a betegek többségében (51/64 = 79,6%), erythropoetin-kezelés történt. Eredmény: A 190 közül 64 betegnél (64/190 = 34%) történt vérátömlesztés a kemoterápia kapcsán kialakult anémia miatt, s az utóbbiaknak csaknem felében (34/64 = 53%) 1-nél több alkalommal végeztek vértranszfúziót. A betegek 86%-ában a vértranszfúzióra G2-súlyosságú anémia miatt került sor. Az ismételten szükséges vértranszfúziókat a leggyakrabban a carboplatin-gemcitabin- (16/16) kezelések után alkalmazták. Következtetés: A petefészekrákokban adott kemoterápiák a betegek harmadában okoznak 10 g%-nál súlyosabb fokú anémiát. A vérszegénység kezelésében a vértranszfúzión kívül gondolni kell az erythropoetin-készítmények alkalmazására.

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