scholarly journals High Antitumor Activity of the Dual Topoisomerase Inhibitor P8-D6 in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 2
Author(s):  
Inken Flörkemeier ◽  
Tamara N. Steinhauer ◽  
Nina Hedemann ◽  
Jörg Paul Weimer ◽  
Christoph Rogmans ◽  
...  

Breast cancer constitutes the leading cause of cancer deaths among females. However, numerous shortcomings, including low bioavailability, resistance and significant side effects, are responsible for insufficient treatment. The ultimate goal, therefore, is to improve the success rates and, thus, the range available treatment options for breast cancer. Consequently, the identification, development and evaluation of potential novel drugs such as P8-D6 with seminal antitumor capacities have a high clinical need. P8-D6 effectively induces apoptosis by acting as a dual topoisomerase I/II inhibitor. This study provides an overview of the effectiveness of P8-D6 in breast cancer with both 2D monolayers and 3D spheroids compared to standard therapeutic agents. For this drug effectiveness review, cell lines and ex vivo primary cells were used and cytotoxicity, apoptosis rates and membrane integrity were examined. This study provides evidence for a significant P8-D6-induced increase in apoptosis and cytotoxicity in breast cancer cells compared to the efficacy of standard therapeutic drugs. To sum up, P8-D6 is a fast and powerful inductor of apoptosis and might become a new and suitable therapeutic option for breast cancer in the future.

Author(s):  
Lisa Agnello ◽  
Silvia Tortorella ◽  
Annachiara d’Argenio ◽  
Clarissa Carbone ◽  
Simona Camorani ◽  
...  

Abstract Background Management of triple-negative breast cancer (TNBC) is still challenging because of its aggressive clinical behavior and limited targeted treatment options. Cisplatin represents a promising chemotherapeutic compound in neoadjuvant approaches and in the metastatic setting, but its use is limited by scarce bioavailability, severe systemic side effects and drug resistance. Novel site-directed aptamer-based nanotherapeutics have the potential to overcome obstacles of chemotherapy. In this study we investigated the tumor targeting and the anti-tumorigenic effectiveness of novel cisplatin-loaded and aptamer-decorated nanosystems in TNBC. Methods Nanotechnological procedures were applied to entrap cisplatin at high efficacy into polymeric nanoparticles (PNPs) that were conjugated on their surface with the epidermal growth factor receptor (EGFR) selective and cell-internalizing CL4 aptamer to improve targeted therapy. Internalization into TNBC MDA-MB-231 and BT-549 cells of aptamer-decorated PNPs, loaded with BODIPY505-515, was monitored by confocal microscopy using EGFR-depleted cells as negative control. Tumor targeting and biodistribution was evaluated by fluorescence reflectance imaging upon intravenously injection of Cyanine7-labeled nanovectors in nude mice bearing subcutaneous MDA-MB-231 tumors. Cytotoxicity of cisplatin-loaded PNPs toward TNBC cells was evaluated by MTT assay and the antitumor effect was assessed by tumor growth experiments in vivo and ex vivo analyses. Results We demonstrate specific, high and rapid uptake into EGFR-positive TNBC cells of CL4-conjugated fluorescent PNPs which, when loaded with cisplatin, resulted considerably more cytotoxic than the free drug and nanovectors either unconjugated or conjugated with a scrambled aptamer. Importantly, animal studies showed that the CL4-equipped PNPs achieve significantly higher tumor targeting efficiency and enhanced therapeutic effects, without any signs of systemic toxicity, compared with free cisplatin and untargeted PNPs. Conclusions Our study proposes novel and safe drug-loaded targeted nanosystems for EGFR-positive TNBC with excellent potential for the application in cancer diagnosis and therapy.


2021 ◽  
Vol 13 ◽  
pp. 175883592110598
Author(s):  
Inken Flörkemeier ◽  
Tamara N. Steinhauer ◽  
Nina Hedemann ◽  
Magnus Ölander ◽  
Per Artursson ◽  
...  

Background: Ovarian cancer (OvCa) constitutes a rare and highly aggressive malignancy and is one of the most lethal of all gynaecologic neoplasms. Due to chemotherapy resistance and treatment limitations because of side effects, OvCa is still not sufficiently treatable. Hence, new drugs for OvCa therapy such as P8-D6 with promising antitumour properties have a high clinical need. The benzo[ c]phenanthridine P8-D6 is an effective inductor of apoptosis by acting as a dual topoisomerase I/II inhibitor. Methods: In the present study, the effectiveness of P8-D6 on OvCa was investigated in vitro. In various OvCa cell lines and ex vivo primary cells, the apoptosis induction compared with standard therapeutic agents was determined in two-dimensional monolayers. Expanded by three-dimensional and co-culture, the P8-D6 treated cells were examined for changes in cytotoxicity, apoptosis rate and membrane integrity via scanning electron microscopy (SEM). Likewise, the effects of P8-D6 on non-cancer human ovarian surface epithelial cells and primary human hepatocytes were determined. Results: This study shows a significant P8-D6-induced increase in apoptosis and cytotoxicity in OvCa cells which surpasses the efficacy of well-established drugs like cisplatin or the topoisomerase inhibitors etoposide and topotecan. Non-cancer cells were affected only slightly by P8-D6. Moreover, no hepatotoxic effect in in vitro studies was detected. Conclusion: P8-D6 is a strong and rapid inductor of apoptosis and might be a novel treatment option for OvCa therapy.


2021 ◽  
Author(s):  
Inken Flörkemeier ◽  
Tamara N. Steinhauer ◽  
Nina Hedemann ◽  
Magnus Ölander ◽  
Per Artursson ◽  
...  

Abstract Background: Ovarian cancer (OvCa) constitutes a rare and highly aggressive malignancy and is one of the most lethal of all gynaecologic neoplasms. Due to chemotherapy resistance and treatment limitations because of side effects, OvCa is still not sufficiently treatable. Hence, new drugs for OvCa therapy such as P8-D6 with promising antitumour properties have a high clinical need. The benzo[c]phenanthridine P8-D6 is an effective inductor of apoptosis by acting as a dual topoisomerase I/II inhibitor. Methods: In the present study, the effectiveness of P8-D6 on OvCa was investigated in vitro. In various OvCa cell lines and ex vivo primary cells, the apoptosis induction compared to standard therapeutic agents was determined in 2D monolayers. Expanded by 3D and co-culture, the P8-D6 treated cells were examined for changes in cytotoxicity, apoptosis rate and membrane integrity via scanning electron microscopy (SEM). Likewise, the effects of P8-D6 on non-cancer human ovarian surface epithelial cells and primary human hepatocytes were determined. Results: This study shows a significant P8-D6-induced increase in apoptosis and cytotoxicity in OvCa cells which surpasses the efficacy of standard therapeutic drugs. Non-cancer cells were affected only slightly by P8-D6. Moreover, no hepatotoxic effect in in vitro studies was detected.Conclusions: P8-D6 is a strong and rapid inductor of apoptosis and might be a novel treatment option for OvCa therapy.


2004 ◽  
Vol 6 (4) ◽  
pp. 1-15 ◽  
Author(s):  
Waseem Qasim ◽  
H. Bobby Gaspar ◽  
Adrian J. Thrasher

Infants born with severe combined immune deficiencies are prone to life-threatening infections and, without treatment, do not survive beyond the first year of life. Haematopoietic stem cell transplantation from a fully matched donor offers the possibility of cure. In the absence of a suitable matched donor, haploidentical transplants from a parental donor may be undertaken, but these are associated with more complications and lower success rates. Recently, an alternative therapeutic option based on retroviral gene delivery has been used to correct X-linked severe combined immune deficiency (SCID-X1) and adenosine deaminase deficiency. Clinical trials have established that in situations where ex vivo gene transfer into haematopoietic progenitor cells confers a strong selective advantage, the procedure is a feasible alternative to haploidentical transplantation, with favourable kinetics of immune reconstitution.


2021 ◽  
Author(s):  
Lisa Agnello ◽  
Silvia Tortorella ◽  
Annachiara d'Argenio ◽  
Clarissa Carbone ◽  
Simona Camorani ◽  
...  

Abstract Background: Management of triple-negative breast cancer (TNBC) is still challenging because of its aggressive clinical behavior and limited targeted treatment options. Cisplatin represents a promising chemotherapeutic compound in neoadjuvant approaches and in the metastatic setting, but its use is limited by scarce bioavailability, severe systemic side effects and drug resistance. Novel site-directed aptamer-based nanotherapeutics have the potential to overcome obstacles of chemotherapy. In this study we investigated the tumor targeting and the anti-tumorigenic effectiveness of novel cisplatin-loaded and aptamer-decorated nanosystems in TNBC.Methods: Nanotechnological procedures were applied to entrap cisplatin at high efficacy into polymeric nanoparticles (PNPs) that were conjugated on their surface with the epidermal growth factor receptor (EGFR) selective and cell-internalizing CL4 aptamer to improve targeted therapy. Internalization into TNBC MDA-MB-231 and BT-549 cells of aptamer-decorated PNPs, loaded with BODIPY505-515, was monitored by confocal microscopy using EGFR-depleted cells as negative control. Tumor targeting and biodistribution was evaluated by fluorescence reflectance imaging upon intravenously injection of Cyanine7-labeled nanovectors in nude mice bearing subcutaneous MDA-MB-231 tumors. Cytotoxicity of cisplatin-loaded PNPs toward TNBC cells was evaluated by MTT assay and the antitumor effect was assessed by tumor growth experiments in vivo and ex vivo analyses.Results: We demonstrate specific, high and rapid uptake into EGFR-positive TNBC cells of CL4-conjugated fluorescent PNPs which, when loaded with cisplatin, resulted considerably more cytotoxic than the free drug and nanovectors either unconjugated or conjugated with a scrambled aptamer. Importantly, animal studies showed that the CL4-equipped PNPs achieve significantly higher tumor targeting efficiency and enhanced therapeutic effects, without any signs of systemic toxicity, compared with free cisplatin and untargeted PNPs.Conclusion: Our study proposes novel and safe drug-loaded targeted nanosystems for EGFR-positive TNBC with excellent potential for the application in cancer diagnosis and therapy.


2018 ◽  
Vol 19 (8) ◽  
pp. 2304 ◽  
Author(s):  
Enrica Chiesa ◽  
Silvia Pisani ◽  
Barbara Colzani ◽  
Rossella Dorati ◽  
Bice Conti ◽  
...  

Selectively targeted nanoscale drug delivery systems have recently emerged as promising intravenously therapeutic option for most chronic joint diseases. Here, a newly synthetized dodecapeptide (GE11)-polylactide-co-glycolide (PLGA)-based conjugate was used to prepare smart nanoparticles (NPs) intended for intra-articular administration and for selectively targeting Epidermal Growth Factor Receptor (EGFR). GE11-PLGA conjugate-based NPs are specifically uptaken by EGFR-overexpressed fibroblast; such as synoviocytes; which are the primarily cellular component involved in the development of destructive joint inflammation. The selective uptake could help to tune drug effectiveness in joints and to decrease local and systemic side effects. Dexamethasone (DXM) is a glucorticoid drug commonly used in joint disease treatment for both systemic and local administration route. In the present research; DXM was efficiently loaded into GE11-PLGA conjugate-based NPs through an eco-friendly nanoprecipitation method set up for this purpose. DXM loaded GE11-PLGA conjugate-based NPs revealed satisfactory ex vivo cytocompatibility; with proper size (≤150 nm) and good dimensional stability in synovial fluid. Intra-articular formulation was developed embedding DXM loaded GE11-PLGA conjugate-based NPs into thermosetting chitosan-based hydrogel; forming a biocompatible composite hydrogel able to quickly turn from liquid state into gel state at physiological temperature; within 15 min. Moreover; the use of thermosetting chitosan-based hydrogel extends the local release of active agent; DXM.


2020 ◽  
Vol 14 (2) ◽  
pp. 87-90
Author(s):  
Sadaf Amin Chaudhry ◽  
Nadia Ali Zafar ◽  
Rabia Hayat ◽  
Ayesha Noreen ◽  
Gulnaz Ali ◽  
...  

Background: Acne is the eighth most prevalent disease affecting 9.4% of the population worldwide and its prevalence in our country is estimated to be around 5%. Severe inflammatory acne is most likely to leave scars and in order to prevent facial disfigurement due to acne scarring, early treatment is desirable. Various treatment options have been formulated for acne, and are tailored according to the severity of the disease. Numerous clinical trials have been conducted till now, to determine the usefulness and side effect profile of such therapies, making acne treatment a highly studied area in dermatology. Objective of this study is to highlight the fact that oral Dapsone could be used as a cheaper alternate to isotretinoin in recalcitrant severe acne, especially in females where retinoids are sometimes contraindicated. Patients and methods: 51 patients, suffering from severe nodulocystic acne, fulfilling the criteria, were enrolled from the Department of Dermatology, Sir Ganga Ram Hospital, Lahore. All the study patients were given oral Dapsone 50mg for initial two weeks and then 100mg daily for the next 10 weeks along with oral cimetidine and topical clindamycin application twice daily. Investigator Global Assessment Scale (IGAS) was employed to measure effectiveness. The treatment was considered ʽeffectiveʹ if the patient achieves 2 or more than 2-grade improvement or almost clear or clear skin at the end of 12 weeks according to IGAS scale. The lesion counts were also done before the start of therapy (day 1) and at every two weeks follow up for 12 weeks. The change in lesion count observed between the baseline number and that seen at follow up visits was also used to evaluate the effectiveness of oral Dapsone. Safety was analyzed by fortnightly visits of the patients to look for any undesirable side effects and monitoring of the hematologic profile of the patients. Final follow up was done at the end of 16 weeks. Results: The study was conducted on 51 patients, with a ratio of 1:3 for males and females and a mean age of 25.2 years (SD ±5.81). At 12th week, patients had significant reduction in their acne lesions; with 7 patients (13.7%) showing completely clear skin, 17 patients (33.3%) had almost clear skin, 5 patients (9.8%) had 3-grade improvement. Twelve patients (23.5%) had 2-grade improvement from baseline score and only 2 patients (3.9%) had 1-grade improvement from baseline. Based on percentage reduction of lesions, excellent response was seen in 32 patients (62.7%), good response in 9 patients (17.6%), moderate response in 2 patients (3.9%), while no patient showed poor response. Dapsone was discontinued in 8 patients due to derangement of hematologic profile. Conclusion: Oral Dapsone, when given carefully, is a very effective therapeutic option in severe recalcitrant acne, with limited side effects.


Author(s):  
Pooja Pathak ◽  
Anand Singh Jalal ◽  
Ritu Rai

Background: Breast cancer represents uncontrolled breast cell growth. Breast cancer is the most diagnosed cancer in women worldwide. Early detection of breast cancer improves the chances of survival and increases treatment options. There are various methods for screening breast cancer such as mammogram, ultrasound, computed tomography, Magnetic Resonance Imaging (MRI). MRI is gaining prominence as an alternative screening tool for early detection and breast cancer diagnosis. Nevertheless, MRI can hardly be examined without the use of a Computer-Aided Diagnosis (CAD) framework, due to the vast amount of data. Objective: This paper aims to cover the approaches used in CAD system for the detection of breast cancer. Method: In this paper, the methods used in CAD systems are categories in two classes: the conventional approach and artificial intelligence (AI) approach. The conventional approach covers the basic steps of image processing such as preprocessing, segmentation, feature extraction and classification. The AI approach covers the various convolutional and deep learning networks used for diagnosis. Conclusion: This review discusses some of the core concepts used in breast cancer and presents a comprehensive review of efforts in the past to address this problem.


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