scholarly journals Kinase-independent inhibition of cyclophosphamide-induced pathways protects the ovarian reserve and prolongs fertility

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Giovanna Bellusci ◽  
Luca Mattiello ◽  
Valentina Iannizzotto ◽  
Sarah Ciccone ◽  
Emiliano Maiani ◽  
...  
Keyword(s):  
Ovarian Reserve ◽  
Protein Kinase B ◽  
Concomitant Administration ◽  
In Vivo Studies ◽  
Cancer Therapies ◽  
Chemotherapeutic Drugs ◽  
Forkhead Box ◽  
Protective Strategy ◽  
Sequential Mechanism

Abstract Premature ovarian failure and infertility are adverse effects of cancer therapies. The mechanism underlying chemotherapy-mediated depletion of the ovarian reserve remains unclear. Here, we aim to identify the signaling pathways involved in the loss of the ovarian reserve to prevent the damaging effects of chemotherapy. We evaluated the effects of cyclophosphamide, one of the most damaging chemotherapeutic drugs, against follicle reserve. In vivo studies showed that the cyclophosphamide-induced loss of ovarian reserve occurred through a sequential mechanism. Cyclophosphamide exposure induced the activation of both DNAPK-γH2AX-checkpoint kinase 2 (CHK2)-p53/TAp63α isoform and protein kinase B (AKT)-forkhead box O3 (FOXO3a) signaling axes in the nucleus of oocytes. Concomitant administration of an allosteric ABL inhibitor and cyclophosphamide modulated both pathways while protecting the ovarian reserve from chemotherapy assaults. As a consequence, the fertility of the treated mice was prolonged. On the contrary, the administration of an allosteric ABL activator enhanced the lethal effects of cyclophosphamide while shortening mouse fertility. Therefore, kinase-independent inhibition may serve as an effective ovarian-protective strategy in women under chemotherapy.

scholarly journals Kinase-independent inhibition of cyclophosphamide-induced pathways protects the ovarian reserve and prolongs fertility

2019 ◽  
Author(s):  
Giovanna Bellusci ◽  
Valentina Iannizzotto ◽  
Sarah Ciccone ◽  
Luca Mattiello ◽  
Emiliano Maiani ◽  
...  
Keyword(s):  
Ovarian Reserve ◽  
Protein Kinase B ◽  
Concomitant Administration ◽  
In Vivo Studies ◽  
Cancer Therapies ◽  
Chemotherapeutic Drugs ◽  
Forkhead Box ◽  
Protective Strategy ◽  
Sequential Mechanism

Premature ovarian failure and infertility are adverse effects of cancer therapies. The mechanism underlying chemotherapy-mediated depletion of the ovarian reserve remains unclear. Here, we aim to identify the signaling pathways involved in the loss of the ovarian reserve to prevent the damaging effects of chemotherapy. We evaluated the effects of cyclophosphamide, one of the most damaging chemotherapeutic drugs, against follicle reserve. In vivo studies showed that the cyclophosphamide-induced loss of ovarian reserve occurred through a sequential mechanism. Cyclophosphamide exposure induced the activation of both DNAPK-γH2AX-checkpoint kinase 2 (CHK2)-p53/TAp63α isoform and protein kinase B (AKT)-forkhead box O3 (FOXO3a) signaling axes in the nucleus of oocytes. Concomitant administration of an allosteric ABL inhibitor and cyclophosphamide modulated both pathways while protecting the ovarian reserve from chemotherapy assaults. As a consequence, the fertility of the treated mice was prolonged. On the contrary, the administration of an allosteric ABL activator enhanced the lethal effects of cyclophosphamide while shortening mouse fertility. Therefore, kinase-independent inhibition may serve as an effective ovarian-protective strategy in women under chemotherapy.

scholarly journals Asciminib Mitigates DNA Damage Stress Signaling Induced by Cyclophosphamide in the Ovary

2021 ◽  
Vol 22 (3) ◽  
pp. 1395
Author(s):  
Luca Mattiello ◽  
Giulia Pucci ◽  
Francesco Marchetti ◽  
Marc Diederich ◽  
Stefania Gonfloni
Keyword(s):  
Ovarian Reserve ◽  
Kinase Inhibitor ◽  
Concomitant Administration ◽  
Cancer Therapies ◽  
Cancer Treatments ◽  
Abl Tyrosine Kinase ◽  
Negative Impacts ◽  
Abl Tyrosine Kinase Inhibitor

Cancer treatments can often adversely affect the quality of life of young women. One of the most relevant negative impacts is the loss of fertility. Cyclophosphamide is one of the most detrimental chemotherapeutic drugs for the ovary. Cyclophosphamide may induce the destruction of dormant follicles while promoting follicle activation and growth. Herein, we demonstrate the in vivo protective effect of the allosteric Bcr-Abl tyrosine kinase inhibitor Asciminib on signaling pathways activated by cyclophosphamide in mouse ovaries. We also provide evidence that Asciminib does not interfere with the cytotoxic effect of cyclophosphamide in Michigan Cancer Foundation (MCF)7 breast cancer cells. Our data indicate that concomitant administration of Asciminib mitigates the cyclophosphamide-induced ovarian reserve loss without affecting the anticancer potential of cyclophosphamide. Taken together, these observations are relevant for the development of effective ferto-protective adjuvants to preserve the ovarian reserve from the damaging effects of cancer therapies.

scholarly journals Asciminib mitigates DNA damage stress signalling induced by cyclophosphamide in the ovary

2020 ◽  
Author(s):  
Luca Mattiello ◽  
Giulia Pucci ◽  
Francesco Marchetti ◽  
Marc Diederich ◽  
Stefania Gonfloni
Keyword(s):  
Ovarian Reserve ◽  
Kinase Inhibitor ◽  
Concomitant Administration ◽  
Cancer Therapies ◽  
Cancer Treatments ◽  
Abl Tyrosine Kinase ◽  
Negative Impacts ◽  
Abl Tyrosine Kinase Inhibitor

AbstractCancer treatments often have adverse effects on the quality of life for young women. One of the most relevant negative impacts is the loss of fertility. Cyclophosphamide is one of the most detrimental chemotherapeutic drugs for the ovary. Cyclophosphamide may induce the destruction of dormant follicles while promoting follicle activation and growth. Herein, we demonstrate the in vivo protective effect of the allosteric Bcr-Abl tyrosine kinase inhibitor Asciminib on signalling pathways activated by cyclophosphamide in mouse ovaries. Besides, we provide evidence that Asciminib did not interfere with the cytotoxic effect of cyclophosphamide in MCF7 breast cancer cells. Our data indicate that concomitant administration of Asciminib mitigates the cyclophosphamide-induced ovarian reserve loss without preventing the anticancer potential of cyclophosphamide. Altogether these observations are relevant for the development of effective ferto-protective adjuvants to preserve the ovarian reserve from the damaging effect of cancer therapies.

scholarly journals Strains, Mechanism, and Perspective:Salmonella-Based Cancer Therapy

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Cheng-Zhi Wang ◽  
Robert A. Kazmierczak ◽  
Abraham Eisenstark
Keyword(s):  
Synthetic Biology ◽  
Tumor Targeting ◽  
Tumor Therapy ◽  
The Other ◽  
Cancer Therapies ◽  
Chemotherapeutic Drugs ◽  
Serovar Typhimurium ◽  
Candidate Strain

Recently, investigation of bacterial-based tumor therapy has regained focus due to progress in molecular, cellular, and microbial biology. Many bacteria such asSalmonella,Listeria,Escherichia, andClostridiumhave proved to have tumor targeting and in some cases even tumor-destroying phenotypes. Furthermore, bacterial clinical treatments for cancer have been improved by combination with other therapeutic methods such as chemotherapeutic drugs and radioactive agents. Synthetic biology techniques have also driven the development of new bacterial-based cancer therapies. However, basic questions about the mechanisms of bacterial-mediated tumor targeting and destruction are still being elucidated. In this review, we focus on three tumor-therapeuticSalmonellamodels, the most intensively studied bacterial genus in this field. One of theseSalmonellamodels is ourSalmonella entericaserovar Typhimurium LT2 derived strain CRC2631, engineered to minimize toxicity but maximize tumor-targeting and destruction effects. The other two are VNP20009 and A1-R. We compare the means by which these therapeutic candidate strain models were selected for study, their tumor targeting and tumor destruction phenotypesin vitroandin vivo, and what is currently known about the mechanisms by which they target and destroy tumors.

BIX-01294-enhanced chemosensitivity in nasopharyngeal carcinoma depends on autophagy-induced pyroptosis

2020 ◽  
Vol 52 (10) ◽  
pp. 1131-1139
Author(s):  
Qian Li ◽  
Min Wang ◽  
Yan Zhang ◽  
Liuqian Wang ◽  
Wei Yu ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Caspase 3 ◽  
Southern China ◽  
Annexin V ◽  
In Vivo Studies ◽  
Cell Swelling ◽  
Chemotherapeutic Drugs ◽  
Double Positive

Abstract Nasopharyngeal carcinoma (NPC) is a common cancer in southern China and Southeast Asia. Nowadays, radiotherapy is the therapy of choice for NPC patients, and chemotherapy has been found as an alternative treatment for advanced NPC patients. However, finding novel drugs and pharmacologically therapeutic targets for NPC patients is still urgent and beneficial. Our study showed that BIX-01294 (BIX) can induce autophagic vacuoles formation and conversion of LC3B-I to LC3B-II in NPC cells in both dose- and time-dependent manners. Notably, the combination of BIX and chemotherapeutic drugs significantly decreased the cell viability and increased the lactate dehydrogenase release. Meanwhile, BIX plus cis-platinum (Cis) treatment induced pyroptosis in NPC cells as featured by cell swelling and bubble blowing from the plasma membrane, the increased frequency of annexin V and propidium iodide (PI) double-positive cells, as well as the cleavage of gasdermin E (GSDME) and caspase-3. Moreover, the deficiency of GSDME completely shifted pyroptosis to apoptosis. Furthermore, the inhibition of autophagy by chloroquine and the knockout of ATG5 gene significantly blocked the BIX-induced autophagy as well as pyroptosis in both in vitro and in vivo studies. Our data demonstrated that BIX-combined chemotherapeutic drugs could induce the Bax/caspase-3/GSDME-mediated pyroptosis through the activation of autophagy to enhance the chemosensitivity in NPC.

scholarly journals Phycocyanin from Arthrospira platensis as Potential Anti-Cancer Drug: Review of In Vitro and In Vivo Studies

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 91
Author(s):  
Steffen Braune ◽  
Anne Krüger-Genge ◽  
Sarah Kammerer ◽  
Friedrich Jung ◽  
Jan-Heiner Küpper
Keyword(s):  
Molecular Mechanisms ◽  
Arthrospira Platensis ◽  
Water Soluble ◽  
In Vivo Studies ◽  
Cancer Drug ◽  
Cancer Therapies ◽  
Natural Substances ◽  
Anti Cancer

The application of cytostatic drugs or natural substances to inhibit cancer growth and progression is an important and evolving subject of cancer research. There has been a surge of interest in marine bioresources, particularly algae, as well as cyanobacteria and their bioactive ingredients. Dried biomass products of Arthrospira and Chlorella have been categorized as “generally recognized as safe” (GRAS) by the US Food and Drug Administration (FDA). Of particular importance is an ingredient of Arthrospira: phycocyanin, a blue-red fluorescent, water-soluble and non-toxic biliprotein pigment. It is reported to be the main active ingredient of Arthrospira and was shown to have therapeutic properties, including anti-oxidant, anti-inflammatory, immune-modulatory and anti-cancer activities. In the present review, in vitro and in vivo data on the effects of phycocyanin on various tumor cells and on cells from healthy tissues are summarized. The existing knowledge of underlying molecular mechanisms, and strategies to improve the efficiency of potential phycocyanin-based anti-cancer therapies are discussed.

Anti-Cancer Effect of Gingerol in Cancer Prevention and Treatment

2020 ◽  
Vol 20 ◽  
Author(s):  
Sana Nafees ◽  
Md. Zafaryab ◽  
Syed H. Mehdi ◽  
Bushra Zia ◽  
Moshahid A. Rizvi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Zingiber Officinale ◽  
Basic Mechanism ◽  
In Vivo Studies ◽  
Cancer Therapies ◽  
Beneficial Effects ◽  
Proinflammatory Mediators ◽  
Natural Agents

: Cancer is one of the most lethal diseases in the world. Because of high death rate associated with cancer and the side effects of chemotherapy and radiation therapy, patients required alternative strategies for its treatment. Ginger (Zingiber officinale) has an enormous medicinal properties and health beneficial effects. In this review, we discuss the basic mechanism by which gingerol (a active component of ginger) modulate a variety of cell signaling pathways linked to cancer, including nuclear factors (NF-κB), signal transducer and activator of transcription 3 (STAT3), activator protein1 (AP-1), β- catenin, growth factors receptors (EGFR, VEGFR); mitogen activated protein kinases (MAPK) and proinflammatory mediators (TNF-α and COX-2). Both in vitro and in vivo studies support the role of gingerol in cancer. The efficacy of gingerol by clinical trials has also been reported. Importantly, natural agents are already in clinical trials against various kinds of cancer. Effort has been made through this comprehensive review to highlight the recent developments and milestones achieved in cancer therapies via studies based on different cell lines using gingerol.

scholarly journals Paclitaxel-Loaded Magnetic Nanoparticles Based on Biotinylated N-Palmitoyl Chitosan: Synthesis, Characterization and Preliminary In Vitro Studies

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3467
Author(s):  
Vlad Constantin Ursachi ◽  
Gianina Dodi ◽  
Alina Gabriela Rusu ◽  
Cosmin Teodor Mihai ◽  
Liliana Verestiuc ◽  
...  
Keyword(s):  
Magnetic Nanoparticles ◽  
Chemotherapeutic Agent ◽  
Magnetic Core ◽  
In Vivo Studies ◽  
Chemotherapeutic Drugs ◽  
Polymeric Surface ◽  
Tumor Recognition ◽  
Surface Shell

A considerable interest in cancer research is represented by the development of magnetic nanoparticles based on biofunctionalized polymers for controlled-release systems of hydrophobic chemotherapeutic drugs targeted only to the tumor sites, without affecting normal cells. The objective of the paper is to present the synthesis and in vitro evaluation of the nanocomposites that include a magnetic core able to direct the systems to the target, a polymeric surface shell that provides stabilization and multi-functionality, a chemotherapeutic agent, Paclitaxel (PTX), and a biotin tumor recognition layer. To our best knowledge, there are no studies concerning development of magnetic nanoparticles obtained by partial oxidation, based on biotinylated N-palmitoyl chitosan loaded with PTX. The structure, external morphology, size distribution, colloidal and magnetic properties analyses confirmed the formation of well-defined crystalline magnetite conjugates, with broad distribution, relatively high saturation magnetization and irregular shape. Even if the ability of the nanoparticles to release the drug in 72 h was demonstrated, further complex in vitro and in vivo studies will be performed in order to validate the magnetic nanoparticles as PTX delivery system.

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