scholarly journals Preparation, Biosafety, and Cytotoxicity Studies of a Newly Tumor-Microenvironment-Responsive Biodegradable Mesoporous Silica Nanosystem Based on Multimodal and Synergistic Treatment

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Zelai He ◽  
Huijun Zhang ◽  
Hongwei Li ◽  
Yanyan Wang ◽  
Jing Qian ◽  
...  
Keyword(s):  
Particle Size ◽  
Mesoporous Silica ◽  
Tumor Cells ◽  
Blood Compatibility ◽  
Drug Loading ◽  
Physicochemical Characterization ◽  
Antitumor Effects ◽  
Cytotoxicity Studies

Patients with triple negative breast cancer (TNBC) often suffer relapse, and clinical improvements offered by radiotherapy and chemotherapy are modest. Although targeted therapy and immunotherapy have been a topic of significant research in recent years, scientific developments have not yet translated to significant improvements for patients with TNBC. In view of these current clinical treatment shortcomings, we designed a silica nanosystem (SNS) with Nano-Ag as the core and a complex of MnO2 and doxorubicin (Dox) as the surrounding mesoporous silica shell. This system was coated with anti-PD-L1 to target the PD-L1 receptor, which is highly expressed on the surface of tumor cells. MnO2 itself has been shown to act as chemodynamic therapy (CDT), and Dox is cytotoxic. Thus, the full SNS system presents a multimodal, potentially synergistic strategy for the treatment of TNBC. Given potential interest in the clinical translation of SNS, the biological safety and antitumor activity of SNS were evaluated in a series of studies that included physicochemical characterization, particle stability, blood compatibility, and cytotoxicity. We found that the particle size and zeta potential of SNS were 94.6 nm and -22.1 mV, respectively. Ultraviolet spectrum analysis showed that Nano-Ag, Dox, and MnO2 were successfully loaded into SNS, and the drug loading ratio of Dox was about 10.2%. Stability studies found that the particle size of SNS did not change in different solutions. Hemolysis tests showed that SNS, at levels far exceeding the anticipated physiologic concentrations, did not induce red blood cell lysis. Further in vitro and in vivo experiments found that SNS did not activate platelets or cause coagulopathy and had no significant effects on the total number of blood cells or hepatorenal function. Cytotoxicity experiments suggested that SNS significantly inhibited the growth of tumor cells by damaging cell membranes, increasing intracellular ROS levels, inhibiting the release of TGF-β1 cytokines by macrophages, and inhibiting intracellular protein synthesis. In general, SNS appeared to have favorable biosafety and antitumor effects and may represent an attractive new therapeutic approach for the treatment of TNBC.

scholarly journals Effect of Micelle-Incorporated Cisplatin With Sizes Ranging From 8 to 40 nm for the Therapy of Lewis Lung Carcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhicheng Wang ◽  
Yumin Li ◽  
Tong Zhang ◽  
Hongxia Li ◽  
Zhao Yang ◽  
...  
Keyword(s):  
Block Copolymers ◽  
Lung Carcinoma ◽  
Lewis Lung Carcinoma ◽  
Drug Loading ◽  
Complexation Reaction ◽  
Lewis Lung ◽  
Antitumor Effects ◽  
Lung Carcinoma Cells

Insufficient transport of therapeutic cargo into tumor bed is a bottleneck in cancer nanomedicine. Block copolymers are promising carriers with smaller particle size by ratio modification. Here, we constructed cisplatin nanoparticles with sizes ranging from 8 to 40 nm to study the permeability and therapy of Lewis lung carcinoma. We synthesized methoxypoly(ethylene glycol)2000-block poly(L-glutamic acid sodium salt)1979 loading cisplatin through complexation reaction. The cisplatin nanomedicine has high drug loading and encapsulation efficiency. In vitro data demonstrated that cisplatin nanoparticles had equivalent growth-inhibiting effects on Lewis lung carcinoma cells compared to free cisplatin. In vivo evidences showed cisplatin nanoparticles had superior antitumor effects on the Lewis lung carcinoma mouse model with no obvious side effects. All results indicated that optimizing the ratio of block copolymers to obtain smaller sized nanomedicine could act as a promising strategy for overcoming the inadequate accumulation in poorly vascularized tumors.

scholarly journals Hydroxychloroquine Synergizes With The PI3K Inhibitor BKM120 to Exhibit Antitumor Efficacy Independent of Autophagy

2021 ◽  
Author(s):  
Xin Peng ◽  
Shaolu Zhang ◽  
Wenhui Jiao ◽  
Zhenxing Zhong ◽  
Yuqi Yang ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Single Agent ◽  
Antitumor Efficacy ◽  
Antitumor Effects ◽  
Autophagy Inhibitor

Abstract Background: The critical role of phosphoinositide 3-kinase (PI3K) activation in tumor cell biology has prompted massive efforts to develop PI3K inhibitors (PI3Kis) for cancer therapy. However, recent results from clinical trials have shown only a modest therapeutic efficacy of single-agent PI3Kis in solid tumors. Targeting autophagy has controversial context-dependent effects in cancer treatment. As a FDA-approved lysosomotropic agent, hydroxychloroquine (HCQ) has been well tested as an autophagy inhibitor in preclinical models. Here, we elucidated the novel mechanism of HCQ alone or in combination with PI3Ki BKM120 in the treatment of cancer.Methods: The antitumor effects of HCQ and BKM120 on three different types of tumor cells were assessed by in vitro PrestoBlue assay, colony formation assay and in vivo zebrafish and nude mouse xenograft models. The involved molecular mechanisms were investigated by MDC staining, LC3 puncta formation assay, immunofluorescent assay, flow cytometric analysis of apoptosis and ROS, qRT-PCR, Western blot, comet assay, homologous recombination (HR) assay and immunohistochemical staining. Results: HCQ significantly sensitized cancer cells to BKM120 in vitro and in vivo. Interestingly, the sensitization mediated by HCQ could not be phenocopied by treatment with other autophagy inhibitors (Spautin-1, 3-MA and bafilomycin A1) or knockdown of the essential autophagy genes Atg5/Atg7, suggesting that the sensitizing effect might be mediated independent of autophagy status. Mechanistically, HCQ induced ROS production and activated the transcription factor NRF2. In contrast, BKM120 prevented the elimination of ROS by inactivation of NRF2, leading to accumulation of DNA damage. In addition, HCQ activated ATM to enhance HR repair, a high-fidelity repair for DNA double-strand breaks (DSBs) in cells, while BKM120 inhibited HR repair by blocking the phosphorylation of ATM and the expression of BRCA1/2 and Rad51. Conclusions: Our study revealed that HCQ and BKM120 synergistically increased DSBs in tumor cells and therefore augmented apoptosis, resulting in enhanced antitumor efficacy. Our findings provide a new insight into how HCQ exhibits antitumor efficacy and synergizes with PI3Ki BKM120, and warn that one should consider the “off target” effects of HCQ when used as autophagy inhibitor in the clinical treatment of cancer.

scholarly journals Considerable Improvement of Ursolic Acid Water Solubility by Its Encapsulation in Dendrimer Nanoparticles: Design, Synthesis and Physicochemical Characterization

Nanomaterials ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 2196 ◽  
Author(s):  
Silvana Alfei ◽  
Anna Maria Schito ◽  
Guendalina Zuccari
Keyword(s):  
Ursolic Acid ◽  
Water Solubility ◽  
Drug Loading ◽  
Physicochemical Characterization ◽  
Systemic Toxicity ◽  
Water Soluble ◽  
Design Synthesis ◽  
Pentacyclic Triterpenoid

Ursolic acid (UA) is a pentacyclic triterpenoid found in many medicinal plants and aromas endowed with numerous in vitro pharmacological activities, including antibacterial effects. Unfortunately, UA is poorly administered in vivo, due to its water insolubility, low bioavailability, and residual systemic toxicity, thus making urgent the development of water-soluble UA formulations. Dendrimers are nonpareil macromolecules possessing highly controlled size, shape, and architecture. In dendrimers with cationic surface, the contemporary presence of inner cavities and of hydrophilic peripheral functions, allows to encapsulate hydrophobic non-water-soluble drugs as UA, to enhance their water-solubility and stability, and to promote their protracted release, thus decreasing their systemic toxicity. In this paper, aiming at developing a new UA-based antibacterial agent administrable in vivo, we reported the physical entrapment of UA in a biodegradable not cytotoxic cationic dendrimer (G4K). UA-loaded dendrimer nanoparticles (UA-G4K) were obtained, which showed a drug loading (DL%) much higher than those previously reported, a protracted release profile governed by diffusion mechanisms, and no cytotoxicity. Also, UA-G4K was characterized by principal components analysis (PCA)-processed FTIR spectroscopy, by NMR and elemental analyses, and by dynamic light scattering experiments (DLS). The water solubility of UA-G4K was found to be 1868-fold times higher than that of pristine UA, thus making its clinical application feasible.

scholarly journals Tumor Energy Metabolism and Potential of 3-Bromopyruvate as an Inhibitor of Aerobic Glycolysis: Implications in Tumor Treatment

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 317 ◽  
Author(s):  
Tengjiao Fan ◽  
Guohui Sun ◽  
Xiaodong Sun ◽  
Lijiao Zhao ◽  
Rugang Zhong ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Tumor Cells ◽  
Cultured Cells ◽  
Aerobic Glycolysis ◽  
Underlying Mechanism ◽  
Human Case ◽  
Tumor Formation ◽  
Antitumor Effects

Tumor formation and growth depend on various biological metabolism processes that are distinctly different with normal tissues. Abnormal energy metabolism is one of the typical characteristics of tumors. It has been proven that most tumor cells highly rely on aerobic glycolysis to obtain energy rather than mitochondrial oxidative phosphorylation (OXPHOS) even in the presence of oxygen, a phenomenon called “Warburg effect”. Thus, inhibition of aerobic glycolysis becomes an attractive strategy to specifically kill tumor cells, while normal cells remain unaffected. In recent years, a small molecule alkylating agent, 3-bromopyruvate (3-BrPA), being an effective glycolytic inhibitor, has shown great potential as a promising antitumor drug. Not only it targets glycolysis process, but also inhibits mitochondrial OXPHOS in tumor cells. Excellent antitumor effects of 3-BrPA were observed in cultured cells and tumor-bearing animal models. In this review, we described the energy metabolic pathways of tumor cells, mechanism of action and cellular targets of 3-BrPA, antitumor effects, and the underlying mechanism of 3-BrPA alone or in combination with other antitumor drugs (e.g., cisplatin, doxorubicin, daunorubicin, 5-fluorouracil, etc.) in vitro and in vivo. In addition, few human case studies of 3-BrPA were also involved. Finally, the novel chemotherapeutic strategies of 3-BrPA, including wafer, liposomal nanoparticle, aerosol, and conjugate formulations, were also discussed for future clinical application.

scholarly journals In Vivo Biocompatibility of Electrospun Biodegradable Dual Carrier (Antibiotic + Growth Factor) in a Mouse Model—Implications for Rapid Wound Healing

Pharmaceutics ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 180 ◽  
Author(s):  
Charu Dwivedi ◽  
Himanshu Pandey ◽  
Avinash C. Pandey ◽  
Sandip Patil ◽  
Pramod W. Ramteke ◽  
...  
Keyword(s):  
Wound Healing ◽  
Growth Factor ◽  
Drug Loading ◽  
Physicochemical Characterization ◽  
Diabetic Wound ◽  
Scanning Calorimetry ◽  
Rapid Healing ◽  
Diabetic Wound Healing

Tissue engineering technologies involving growth factors have produced one of the most advanced generations of diabetic wound healing solutions. Using this approach, a nanocomposite carrier was designed using Poly(d,l-lactide-co-glycolide) (PLGA)/Gelatin polymer solutions for the simultaneous release of recombinant human epidermal growth factor (rhEGF) and gentamicin sulfate at the wound site to hasten the process of diabetic wound healing and inactivation of bacterial growth. The physicochemical characterization of the fabricated scaffolds was carried out using scanning electron microscopy (SEM) and X-ay diffraction (XRD). The scaffolds were analyzed for thermal stability using thermogravimetric analysis and differential scanning calorimetry. The porosity, biodegradability, and swelling behavior of the scaffolds was also evaluated. Encapsulation efficiency, drug loading capacity, and in vitro drug release were also investigated. Further, the bacterial inhibition percentage and detailed in vivo biocompatibility for wound healing efficiency was performed on diabetic C57BL6 mice with dorsal wounds. The scaffolds exhibited excellent wound healing and continuous proliferation of cells for 12 days. These results support the applicability of such systems in rapid healing of diabetic wounds and ulcers.

scholarly journals T Cells Expressing Engager and Costimulatory Molecules for the Immunotherapy of CD19+ Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2433-2433
Author(s):  
Mireya Paulina Velasquez ◽  
Kota Iwahori ◽  
David L Torres ◽  
Sunitha Kakarla ◽  
Caroline Arber ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Xenograft Model ◽  
Retroviral Vector ◽  
Effector Function ◽  
Target Cells ◽  
Antitumor Effects

Abstract Background: Immunotherapy with anti-CD19/anti-CD3 bispecific engager molecules has shown promise in clinical studies for CD19+ malignancies. However engager molecules have short half-lives and do not accumulate at tumor sites. In addition, co-delivery of other immunostimulatory molecules to enhance antitumor effects is difficult to achieve. We have recently shown that T cells can be genetically modified to secrete bispecific engager molecules (ENG-T cells). ENG-T cells are activated by tumor cells in an antigen-dependent manner, redirect bystander T cells to tumor cells, and have antitumor activity in preclinical models. We now wanted to explore if additional genetic modifications of ENG-T cells can enhance their effector function in vitro and in vivo. Since bispecific engager molecules do not provide co-stimulation, we focused on the provision of co-stimulatory signals by coexpressing CD80 and CD137L on the cell surface of ENG-T cells. Thus, the aim of the study was to compare the effector function of CD19-specific T-cell engagers (CD19-ENG T cells) and CD19-ENG T cells co-expressing CD80 and 41BBL (CD19-ENG/Costim T cells). Methods: CD19-ENG T cells were generated by transducing T cells with a retroviral vector encoding a CD19-specific T-cell engager and mOrange separated by an IRES (SFG.CD19-ENG-I-mO), and CD19-ENG/Costim T cells were generated by double transducing T cells with SFG.CD19-ENG-I-mO and a 2nd retroviral vector encoding 41BBL and CD80 separated by an IRES. The effector function of ENG T-cells was evaluated in vitro and in a leukemia xenograft model. Results: After single or double transduction 60-80% of T cells were positive for mOrange, and ~80% of CD19-ENG/Costim T cells were positive for CD80 and 30-40% positive for 41BBL. In coculture assays CD19-ENG and CD19-ENG/Costim T cells recognized CD19+ lymphoma (Daudi, Raji) and acute leukemia (BV173) cells as judged by IFN-g secretion in contrast to negative controls. While CD19+ target cells that express CD80 and CD86 (Daudi and Raji) induced robust IL2 production of CD19-ENG and CD19-ENG/Costim T cells, CD19-ENG/Costim T cells produced significantly higher levels of IL2 in comparison to CD19-ENG T cells after stimulation with CD19+/CD80-/CD86- negative target cells (BV173). Cytokine production was antigen dependent since ENG and ENG/Costim T cells specific for an irrelevant antigen (EphA2) did not produce cytokines. Specificity was confirmed in cytotoxicity assays. In transwell assays containing inserts preventing T-cell migration, only ENG T cells redirected bystander T cells in the bottom well to CD19+ tumor cells. To assess in vivo anti-tumor activity of CD19-ENG T cells and CD19-ENG/Costim T cells we used the BV173/NSG mouse xenograft model in which BV173 cells are genetically modified with firefly luciferase (ffLuc-BV173) to allow for serial bioluminescence imaging. While therapy with CD19-ENG T cells on day 7 post ffLuc-BV173 injection resulted in the cure of all mice, when therapy was delayed to day 14, only 1/10 mice was alive on day 80. In contrast therapy of mice on day 14 with CD19-ENG/Costim T cells resulted in long-term survival of 7/10 mice. Control T cells (EphA2-ENG T cells or EphA2-ENG/Costim T cells) had no antitumor effects. Conclusions: We have generated CD19-ENG T cells and CD19-ENG/Costim T cells with the ability to direct bystander T cells to CD19+ malignancies. Both ENG T-cell populations had potent antitumor activity in a preclinical ALL model, and provision of costimulation further enhanced antitumor effects. Genetically modifying T cells to express engager molecules and additional molecules to enhance their effector function may present a promising alternative to current CD19-targeted immunotherapies. Disclosures Velasquez: Celgene, Bluebird bio: Other. Iwahori:Celgene, Bluebird bio: Other. Kakarla:Celgene, Bluebird bio: Other. Song:Celgene, Bluebird bio: Other. Gottschalk:Celgene, Bluebird bio: Other.

scholarly journals Spatiotemporal depletion of tumor-associated immune checkpoint PD-L1 with near-infrared photoimmunotherapy promotes antitumor immunity

2021 ◽  
Vol 9 (11) ◽  
pp. e003036
Author(s):  
Shunichi Taki ◽  
Kohei Matsuoka ◽  
Yuko Nishinaga ◽  
Kazuomi Takahashi ◽  
Hirotoshi Yasui ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Immune Checkpoint ◽  
Antitumor Immunity ◽  
Near Infrared ◽  
Specific Antigen ◽  
Cancer Therapeutics ◽  
Antitumor Effects ◽  
Nir Light

BackgroundNear-infrared photoimmunotherapy (NIR-PIT) is a new modality for treating cancer, which uses antibody-photoabsorber (IRDye700DX) conjugates that specifically bind to target tumor cells. This conjugate is then photoactivated by NIR light, inducing rapid necrotic cell death. NIR-PIT needs a highly expressed targeting antigen on the cells because of its reliance on antibodies. However, using antibodies limits this useful technology to only those patients whose tumors express high levels of a specific antigen. Thus, to propose an alternative strategy, we modified this phototechnology to augment the anticancer immune system by targeting the almost low-expressed immune checkpoint molecules on tumor cells.MethodsWe used programmed death-ligand 1 (PD-L1), an immune checkpoint molecule, as the target for NIR-PIT. Although the expression of PD-L1 on tumor cells is usually low, PD-L1 is almost expressed on tumor cells. Intratumoral depletion with PD-L1-targeted NIR-PIT was tested in mouse syngeneic tumor models.ResultsAlthough PD-L1-targeted NIR-PIT showed limited effect on tumor cells in vitro, the therapy induced sufficient antitumor effects in vivo, which were thought to be mediated by the ‘photoimmuno’ effect and antitumor immunity augmentation. Moreover, PD-L1-targeted NIR-PIT induced antitumor effect on non-NIR light-irradiated tumors.ConclusionsLocal PD-L1-targeted NIR-PIT enhanced the antitumor immune reaction through a direct photonecrotic effect, thereby providing an alternative approach to targeted cancer immunotherapy and expanding the scope of cancer therapeutics.

scholarly journals Selectively Targeting Tumor Hypoxia with the Hypoxia-Activated Prodrug CP-506

2021 ◽  
Author(s):  
Alexander M.A. van der Wiel ◽  
Victoria Jackson-Patel ◽  
Raymon Niemans ◽  
Ala Yaromina ◽  
Emily Liu ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Cells ◽  
Tumor Hypoxia ◽  
Human Tumor ◽  
Tumor Oxygenation ◽  
Antitumor Effects ◽  
Wide Range ◽  
Hypoxic Tumor

Abstract Background Hypoxia-activated prodrugs (HAPs) are a promising class of antineoplastic agents that can selectively eliminate hypoxic tumor cells. The present study evaluates the hypoxia-selectivity and antitumor activity of CP-506, a DNA alkylating HAP with favorable pharmacological properties. Methods Stoichiometry of reduction, one-electron affinity, and back-oxidation rate of CP-506 were characterized by fast-reaction radiolytic methods. In vitro, 2D monolayer and 3D spheroid and multicellular layer cultures were used to investigate the hypoxia-selectivity of CP-506. In vivo, the causal relationship between tumor oxygenation and antitumor effects of CP-506 was assessed. Mice bearing a range of human tumor xenografts were exposed to CP-506 and tumor growth was monitored. A multivariate linear regression model was used to identify factors associated with CP-506 treatment outcome. Results Net reduction, metabolism, and cytotoxicity of CP-506 were maximally inhibited at oxygen concentrations above 1 µM (0.1% O2). CP-506 demonstrated cytotoxicity selectively in hypoxic 2D and 3D cell cultures with normoxic/anoxic IC50 ratios up to 203. In vivo, the antitumor effects of CP-506 were selective for hypoxic tumor cells and causally related to tumor oxygenation. CP-506 effectively decreased the hypoxic fraction and inhibited growth of a wide range of hypoxic xenografts. Two well-oxygenated models were refractory to treatment despite intrinsic anoxic sensitivity in vitro. A multivariate regression analysis revealed baseline tumor hypoxia and in vitro sensitivity to CP-506 to significantly correlate with treatment response. Conclusions Our results demonstrate that CP-506 selectively sterilizes hypoxic tumor cells and has broad antitumor activity. Our data also indicate that tumor hypoxia and cellular sensitivity to CP-506 are strong determinants of the antitumor effects of CP-506.

scholarly journals INCREASED LEVEL OF MIR-204-5P EXPRESSION IN MELANOMA CELLS UNDER THE INFLUENCE OF DACARBAZINE

2019 ◽  
Vol 18 (3) ◽  
pp. 45-53
Author(s):  
S. N. Lavrentiev ◽  
M. B. Aksenenko ◽  
A. S. Averchuk ◽  
A. V. Komina ◽  
N. V. Palkina ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Animal Behavior ◽  
Growth Dynamics ◽  
Inhibitory Effect ◽  
Melanoma Cells ◽  
Migration And Invasion ◽  
Antitumor Effects ◽  
Metastasis Development

Various types of tissues was analyzed, and the algorithm for summing neutron and photon doses in neutronMiRNA s are involved in the regulation of numerous critical biological processes, including cell proliferation, differentiation, migration and invasion. They function as oncogenes or tumor suppressors according to the nature of the target. It has been previously determined that miR-204-5p miRNA is characterized by the increased level in melanoma. The aim of this study was to determine the effects of changes in the level of microRNA expression when dacarbazine was exposed to melanoma cells in vitro and synthetic miR-204-5p in vivo. The expression levels of miR-204-5p and miR-211 in melanoma cells were determined by real-time PCR. Antitumor effects in vivo were verified in assessing the growth dynamics of the tumor node. Toxic effects were assessed by animal behavior, fluid intake, feed, and ALT , AST , creatinine, urea levels. In the model of melanoma C57BL6, it was revealed that the introduction of the synthetic miR-204-5p did not cause significant changes in the investigated microRNA in tumor cells. At the same time, the antitumor effects of dacarbazine in melanoma cells in vitro led to an increase in the level of the investigated microRNA by more than 20 times. The results of the study indicated the possibility of compensating the level of miR-204-5p under the influence of cytostatic therapy. Taking into account the previously revealed miR-204-5p inhibitory effect on the proliferation of melanoma cells, we can assume that this miRNA can play a role in maintaining the dermal state of tumor cells. Further studies are required to understand the metastasis development and predict the response to antitumor therapy for melanoma.

scholarly journals Brusatol Inhibits Tumor Growth and Increases the Efficacy of Cabergoline against Pituitary Adenomas

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Zerui Wu ◽  
Yunqiu Xu ◽  
Jiadong Xu ◽  
Jianglong Lu ◽  
Lin Cai ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Pituitary Adenomas ◽  
Pituitary Tumor ◽  
Antitumor Effects ◽  
Human Pituitary ◽  
First Choice ◽  
Mtorc1 Signaling

Cabergoline (CAB) is the first choice for treatment of prolactinoma and the most common subtype of pituitary adenoma. However, drug resistance and lack of effectiveness in other pituitary tumor types remain clinical challenges to this treatment. Brusatol (BT) is known to inhibit cell growth and promote apoptosis in a variety of cancer cells. In our present studies, we investigate the effects of BT on pituitary tumor cell proliferation in vitro and in vivo. BT treatment resulted in an increase in Annexin V-expressing cells and promoted the expression of apoptosis-related proteins in rat and human pituitary tumor cells. Investigation of the mechanism underlying this effect revealed that BT increased the production of reactive oxygen species (ROS) and inhibited the phosphorylation of 4EBP1 and S6K1. Furthermore, treatment with a combination of BT and CAB resulted in greater antitumor effects than either treatment alone in nude mice and pituitary tumor cells. Collectively, our results suggest that the BT-induced ROS accumulation and inhibition of mTORC1 signaling pathway leads to inhibition of tumor growth. Combined use of CAB and BT may increase the clinical effectiveness of treatment for human pituitary adenomas.

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