scholarly journals Exploiting the Anticancer Effects of a Nitrogen Bisphosphonate Nanomedicine for Glioblastoma Multiforme

2020 ◽  
Author(s):  
Lynn Jena ◽  
Lindsey Bennie ◽  
Emma McErlean ◽  
Sreekanth Pentlavalli ◽  
Raj Thakur ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Scale Up ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Anticancer Effects ◽  
Induced Apoptosis ◽  
Nano Formulation ◽  
Dose Dependent

Abstract Glioblastoma multiforme (GBM) is an incurable aggressive brain cancer in which current treatment strategies have demonstrated limited survival benefit. In recent years, nitrogen-containing bisphosphonates (N-BPs) have demonstrated direct anticancer effects in a number of tumour types including GBM. In this study, a nano-formulation with the RALA peptide was used to complex the N-BP, alendronate (ALN) into nanoparticles (NPs) <200 nm for optimal endocytic uptake. Fluorescently labelled AlexaFluor®647 Risedronate was used as a fluorescent analogue to visualise the intracellular delivery of N-BPs in both LN229 and T98G GBM cells. RALA NPs were effectively taken up by GBM where a dose-dependent response was evidenced with potentiation factors of 14.96 and 13.4 relative to ALN alone after 72 h in LN229 and T98G cells, respectively. Furthermore, RALA/ALN NPs at the IC50, significantly decreased colony formation, induced apoptosis and slowed spheroid growth in vitro. In addition, H-Ras membrane localisation was significantly reduced in the RALA/ALN groups compared to ALN or controls, indicative of prenylation inhibition. The RALA/ALN NPs were lyophilised to enhance stability without compromising the physiochemical properties necessary for functionality, highlighting the suitability of the NPs for scale-up and in vivo application. Collectively, these data show the significant potential of RALA/ALN NPs as novel therapeutics in the treatment of GBM.

scholarly journals Synergistic antitumor effect of 5-fluorouracil with the novel LSD1 inhibitor ZY0511 in colorectal cancer

2020 ◽  
Vol 12 ◽  
pp. 175883592093742
Author(s):  
Wen Peng ◽  
Huaqing Zhang ◽  
Shisheng Tan ◽  
Yan Li ◽  
Yang Zhou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Antitumor Effect ◽  
Underlying Mechanism ◽  
Synergistic Antitumor Effect ◽  
Anticancer Effects ◽  
Potential Marker ◽  
And Migration ◽  
Induced Apoptosis

Background: Lysine-specific histone demethylase 1 (LSD1) is a potential target of cancer therapy. In the present study, we aimed to investigate the combined antitumor activity of a novel LSD1 inhibitor (ZY0511) with 5-fluorouracil (5-FU) and elucidate the underlying mechanism in colorectal cancer (CRC). Methods: We evaluated LSD1 expression in CRC tissues from patients who received 5-FU treatment. The synergistic antitumor effect of 5-FU with ZY0511 against human CRC cells was detected both in vitro and in vivo. The underlying mechanism was explored based on mRNA sequencing (mRNA-seq) technology. Results: Overexpression of LSD1 was observed in human CRC tissues, and correlated with CRC development and 5-FU resistance. ZY0511, a novel LSD1 inhibitor, effectively inhibited CRC cells proliferation, both in vitro and in vivo. Notably, the combination of ZY0511 and 5-FU synergistically reduced CRC cells viability and migration in vitro. It also suppressed Wnt/β-catenin signaling and DNA synthesis pathways, which finally induced apoptosis of CRC cells. In addition, the combination of ZY0511 with 5-FU significantly reduced CRC xenograft tumor growth, along with lung and liver metastases in vivo. Conclusions: Our findings identify LSD1 as a potential marker for 5-FU resistance in CRC. ZY0511 is a promising candidate for CRC therapy as it potentiates 5-FU anticancer effects, thereby providing a new combinatorial strategy for treating CRC.

Pralatrexate Has Potent Activity Against Multiple Myeloma In Vitro and In Vivo, and Activity Correlates with Tumor RFC-1 and DHFR Expression

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1831-1831 ◽  
Author(s):  
Michael Mangone ◽  
Luigi Scotto ◽  
Enrica Marchi ◽  
Owen A. O'Connor ◽  
Hearn J. Cho
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Research Funding ◽  
Folate Metabolism ◽  
Nog Mice ◽  
Induced Apoptosis ◽  
Dose Dependent ◽  
Functional Biomarkers

Abstract Abstract 1831 Multiple myeloma (MM) is the second most common hematologic malignancy. Although there are effective new agents that can induce remission, relapse is inevitable and the disease is currently incurable. Progress in the treatment of this disease demands development of novel therapeutics and identification of functional biomarkers that may be used to distinguish tumors that are susceptible to specific targeted agents, creating a “personalized” therapeutic strategy for individual patients. We investigated these principles with anti-folates, which are not commonly used in MM but have demonstrated activity in this disease. Pralatrexate (PDX, 10-propargyl 10-deazaaminopterin) is a folate analogue that was rationally designed to have high affinity for Reduced Folate Carrier (RFC)-1, an oncofetal protein expressed in many cancers that actively transports folates into cells. PDX induced dose-dependent apoptotic cell death in a subset of human myeloma cell lines (HMCL) and CD138+ MM cells isolated from a clinical specimen. In sensitive cell lines, PDX exhibited 10-fold greater potency compared to the structurally related drug methotrexate (MTX). PDX induced dose-dependent, intrinsic apoptosis in sensitive HMCLs, characterized by cleavage of caspase-3 and -9 and accompanied by the loss of full-length Mcl-1, a Bcl-2 family protein that plays a critical role in drug-induced apoptosis in MM. Furthermore, the activity of PDX is not abrogated by the presence of exogenous interleukin-6 or by co-culture with HS-5 bone marrow stromal cells, both of which exert powerful survival effects on MM cells and can antagonize apoptosis in response to some cytotoxic chemotherapy drugs. Sensitivity to PDX-induced apoptosis correlated with higher relative levels of RFC-1 mRNA in sensitive compared to resistant HMCL. Resistant HMCL also exhibited a dose-dependent up-regulation of dihydrofolate reductase (DHFR) protein, a primary molecular target for anti-folates, in response to PDX exposure, whereas sensitive HMCL did not. These changes in functional folate metabolism biomarkers, high baseline RFC-1 expression and upregulation of DHFR in response to PDX, appeared to be mutually exclusive to sensitive or resistant HMCL, respectively. Importantly, PDX was also effective against sensitive HMCL in vivo in a novel mouse xenograft model. NOD/Shi-scid/IL-2Rγnull (NOG) mice were inoculated with MM.1s HMCL stably transduced to express both GFP and luciferase (GFP-luc). GFP-luc MM.1s cells engrafted into the long bones, pelvis, and vertebral column of NOG mice within 4–7 days after injection of cells, as assessed by in vivo bioluminescent imaging. Treatment with PDX resulted in a significant reduction in tumor burden after two doses. These results demonstrate that PDX has potent anti-myeloma activity in vitro and in vivo, and that RFC-1 expression and DHFR upregulation are robust functional biomarkers that may identify patients who are likely to benefit from PDX therapy. These data support further exploration of PDX therapy in clinical trials for MM and investigation of folate metabolism biomarkers as indices for treatment with this class of drugs. Improved anti-folates such as PDX are a promising class of agents that may be a valuable addition to the arsenal against MM. Disclosures: O'Connor: Celgene: Consultancy, Research Funding; Merck: Research Funding; Novartis: Research Funding; Spectrum: Research Funding.

scholarly journals SLC25A21 Suppresses Cell Growth in Bladder Cancer Via The Reactive Oxygen Species-Mediated Mitochondrion-Dependent Apoptosis Pathway

2021 ◽  
Author(s):  
Yong Wang ◽  
Jiawen Gao ◽  
Shasha Hu ◽  
Weiting Zeng ◽  
Hongjun Yang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Treatment Strategies ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Apoptosis Pathway ◽  
Normal Tissues ◽  
Induced Apoptosis ◽  
New Diagnosis

Abstract Background: Bladder cancer (BCa) is a commonly diagnosed malignancy worldwide that has poor survival depending on its intrinsic biologic aggressiveness and a peculiar radio- and chemoresistance features. Gaining a better understanding of tumorigenesis and developing new diagnosis and treatment strategies for BCa is important for improving BCa clinical outcome. SLC25 family member 21 (SLC25A21), a carrier transporting C5-C7 oxodicarboxylates, has been reported to contribute to oxoadipate acidemia. However, the potential role of SLC25A21 in cancer remains absolutely unknown. Methods: The expression levels of SLC25A21 in BCa and normal tissues were examined by real-time PCR and immunohistochemistry. Gain-of- and loss-of-function experiments were performed to detect the biological functions of SLC25A21 in vitro and in vivo by CCK-8 assay, plate colony formation assay, cell migration, invasion assay and experimental animal models. The subcellular distribution of substrate mediated by SLC25A21, mitochondrial membrane potential and ROS production were assessed to explore the potential mechanism of SLC25A21 in BCa.Results: We found that the expression of SLC25A21 was downregulated in BCa tissues compared to normal tissues. A significant positive correlation between decreased SLC25A21 expression and poor prognosis was observed in BCa patients. Overexpression of SLC25A21 significantly inhibited cell proliferation, migration and invasion and induced apoptosis in vitro. Moreover, the enhanced SLC25A21 expression significantly suppressed tumor growth in a xenograft mouse model. Furthermore, we revealed that SLC25A21 suppressed BCa growth by inducing the efflux of mitochondrial α-KG to the cytosol, decreasing to against oxidative stress, and activating the ROS-mediated mitochondrion-dependent apoptosis pathway. Conclusions: Our findings provide the first link between SLC25A21 expression and BCa and demonstrate that SLC25A21 acts as a crucial suppressor in BCa progression, which may help to provide new targets for BCa intervention.

Anticancer effects of ginsenoside Rk3 on non-small cell lung cancer cells: in vitro and in vivo

2017 ◽  
Vol 8 (10) ◽  
pp. 3723-3736 ◽  
Author(s):  
Zhiguang Duan ◽  
Jianjun Deng ◽  
Yangfang Dong ◽  
Chenhui Zhu ◽  
Weina Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Death Receptor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Anticancer Effects ◽  
Induced Apoptosis

Ginsenoside-Rk3 inhibited proliferation, arrested the cell cycle, induced apoptosisviadeath receptor-mediated mitochondria-dependent pathways and suppressed angiogenesis and tumor growth.

scholarly journals Tauroursodeoxycholic acid prevents Burkholderia pseudomallei-induced endoplasmic reticulum stress and is protective during melioidosis in mice

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Siqi Yuan ◽  
Yao Fang ◽  
Mengling Tang ◽  
Zhiqiang Hu ◽  
Chenglong Rao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Burkholderia Pseudomallei ◽  
Treatment Strategies ◽  
Effective Vaccine ◽  
Tauroursodeoxycholic Acid ◽  
Raw264.7 Macrophages ◽  
Induced Apoptosis

Abstract Background Burkholderia pseudomallei, a facultative intracellular bacterium, is the aetiological agent of melioidosis that is responsible for up to 40% sepsis-related mortality in epidemic areas. However, no effective vaccine is available currently, and the drug resistance is also a major problem in the treatment of melioidosis. Therefore, finding new clinical treatment strategies in melioidosis is extremely urgent. Results We demonstrated that tauroursodeoxycholic acid (TUDCA), a clinically available endoplasmic reticulum (ER) stress inhibitor, can promote B. pseudomallei clearance both in vivo and in vitro. In this study, we investigated the effects of TUDCA on the survival of melioidosis mice, and found that treatment with TUDCA significantly decreased intracellular survival of B. pseudomallei. Mechanistically, we found that B. pseudomallei induced apoptosis and activated IRE1 and PERK signaling ways of ER stress in RAW264.7 macrophages. TUDCA treatment could reduce B. pseudomallei-induced ER stress in vitro, and TUDCA is protective in vivo. Conclusion Taken together, our study has demonstrated that B. pseudomallei infection results in ER stress-induced apoptosis, and TUDCA enhances the clearance of B. pseudomallei by inhibiting ER stress-induced apoptosis both in vivo and in vitro, suggesting that TUDCA could be used as a potentially alternative treatment for melioidosis.

scholarly journals Bortezomib potentiates antitumor activity of Mitoxantrone through dampening Wnt/β-catenin signaling pathway in prostate cancel cells

2021 ◽  
Author(s):  
Ying Zhang ◽  
Qiuzi Liu ◽  
Wei Wei ◽  
Guoan Zhang ◽  
Siyuan Yan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Signaling Pathway ◽  
Target Genes ◽  
Proliferation Assay ◽  
Prostate Cancer Cells ◽  
Anticancer Effects ◽  
Induced Apoptosis

Abstract Background Bortezomib (BZM), alone or in combination with other chemotherapies, has displayed strong anticancer effects in several cancers. The efficacy of the combination of BZM and mitoxantrone (MTX) in treating prostate cancer remains unknown.Methods Anticancer effects of combination of BZM and MTX were determined by apoptosis and proliferation assay in vivo and in vitro. Expression of β-catenin and its target genes were characterized by western blot and Real-time PCR.Results BZM significantly enhanced MTX-induced antiproliferation in vivo and in vitro. Mice administered a combination of BZM and MTX displayed attenuated tumor growth and prolonged survival. BZM significantly attenuated MTX-induced apoptosis. Moreover, the combination of BZM and MTX contributed to inhibition of the Wnt/β-catenin signaling pathway compared to monotherapy.Conclusions This study demonstrates that BZM enhances MTX-induced anti-tumor effects by inhibiting the Wnt/β-catenin signaling pathway in prostate cancer cells.

scholarly journals Bortezomib potentiates antitumor activity of mitoxantrone through dampening Wnt/β-catenin signal pathway in prostate cancer cells

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ying Zhang ◽  
Qiuzi Liu ◽  
Wei Wei ◽  
Guoan Zhang ◽  
Siyuan Yan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Target Genes ◽  
Signal Pathway ◽  
Prostate Cancer Cells ◽  
Anticancer Effects ◽  
Induced Apoptosis

Abstract Background Bortezomib (BZM), alone or in combination with other chemotherapies, has displayed strong anticancer effects in several cancers. The efficacy of the combination of BZM and mitoxantrone (MTX) in treating prostate cancer remains unknown. Methods Anticancer effects of combination of BZM and MTX were determined by apoptosis and proliferation assay in vivo and in vitro. Expression of β-Catenin and its target genes were characterized by western blot and Real-time PCR. Results BZM significantly enhanced MTX-induced antiproliferation in vivo and in vitro. Mice administered a combination of BZM and MTX displayed attenuated tumor growth and prolonged survival. BZM significantly attenuated MTX-induced apoptosis. Moreover, the combination of BZM and MTX contributed to inhibition of the Wnt/β-Catenin signaling pathway compared to monotherapy. Conclusions This study demonstrates that BZM enhances MTX-induced anti-tumor effects by inhibiting the Wnt/β-Catenin signaling pathway in prostate cancer cells.

Carfilzomib, An Irreversible Proteasome Inhibitor, Induces Long-Term Growth Inhibition of Mantle Cell Lymphoma In Vivo,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3740-3740
Author(s):  
Liang Zhang ◽  
Jianfei Qian ◽  
Zhishuo Ou ◽  
Luhong Sun ◽  
Kejie Zhang ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Proteasome Inhibitor ◽  
Cell Lymphoma ◽  
Proteasome Inhibitors ◽  
Dependent Manner ◽  
Mantle Cell ◽  
Induced Apoptosis ◽  
Dose Dependent

Abstract Abstract 3740 Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor clinical outcome, thus, novel therapeutic agents are urgently needed. The proteasome inhibitors are small molecular agents which show significant anti-tumor effect in patients with relapsed/refractory MCL. Carfilzomib, an irreversible proteasome inhibitor with selectivity for the chymotrypsin-like active site, inhibits the proliferation of MCL cells in vitro, as well as the reversible proteasome inhibitor bortezomib. Unlike bortezomib, carfilzomib is good-tolerated and does not induce severe neuropathy in patients. Therefore, carfilzomib can be used in higher dose than bortezomib in vivo. Our study was undertaken to evaluate the therapeutic efficacy of carfilzomib on MCL cells both in vitro and in vivo compared with bortezomib. Four human MCL cell lines, MINO, Jeko-1, MAVER, and NCEB-1, freshly isolated primary MCL cells from the patients with relapsed/refractory MCL, were treated with carfilzomib or bortezomib. A 3H-thymidine incorporation assay showed that both carfilzomib and bortezomib displayed the same dose-dependent manner in inducing growth inhibition of the MCL cells. Similarly, flow cytometry analysis with fluorescence-labeled Annexin V and propidium iodide showed that carfilzomib induced apoptosis of MCL cells in the same dose-dependent manner with bortezomib. However, under the tolerable dose of each of the two proteasome inhibitors, they had different therapeutic effect in a MCL-bearing mouse model established in severe combined immunodeficient (SCID) mice. MINO cells (5 × 106) were inoculated subcutaneously into the right flank of SCID mice. Three weeks later, after palpable tumors developed, mice were treated intravenously with carfilzomib (5 mg/kg) on day 1 and day2, for 5 cycles, or treated intraperitoneally with bortezomib (1 mg/kg) on days 1, 4, 7 and 10, per 21 days. Tumor growth was almost abrogated after treatment with carfilzomib compared with bortezomib, and the survival time of tumor-bearing mice was significantly prolonged in the carfilzomib-treated mice versus bortezomib-treated mice. Notably, Increasing the frequency or dose of bortezomib treatment was unable because the mice were too suffered in toxicity to tolerate the treatment. Western blot analysis showed that carfilzomib induced apoptosis in caspase-dependent manner as well as bortezomib. Carfilzomib inhibited the phosphorylation of IκB, STAT3, and AKT and irreversibly blocked the release of NFκB to nuclei. In conclusion, carfilzomib displays the same anti-tumor effect and mechanism with bortezomib on MCL cells in vitro. However, carfilzomib but not bortezomib is well tolerated without severe side effect in vivo. Carfilzomib significantly inhibits tumor growth and prolongs survival indicating that carfilzomib is a potential agent in MCL chemotherapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Peiminine Reduces ARTS-Mediated Degradation of XIAP by Modulating the PINK1/Parkin Pathway to Ameliorate 6-Hydroxydopamine Toxicity and α-Synuclein Accumulation in Parkinson’s Disease Models In Vivo and In Vitro

2021 ◽  
Vol 22 (19) ◽  
pp. 10240
Author(s):  
Yu-Ling Hsu ◽  
Huey-Shan Hung ◽  
Chia-Wen Tsai ◽  
Shih-Ping Liu ◽  
Yu-Ting Chiang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mechanism Of Action ◽  
Treatment Strategies ◽  
Ubiquitin Proteasome System ◽  
Pathologic Features ◽  
Induced Apoptosis ◽  
6 Hydroxydopamine

Parkinson’s disease (PD) is a degenerative disease that can cause motor, cognitive, and behavioral disorders. The treatment strategies being developed are based on the typical pathologic features of PD, including the death of dopaminergic (DA) neurons in the substantia nigra of the midbrain and the accumulation of α-synuclein in neurons. Peiminine (PMN) is an extract of Fritillaria thunbergii Miq that has antioxidant and anti-neuroinflammatory effects. We used Caenorhabditis elegans and SH-SY5Y cell models of PD to evaluate the neuroprotective potential of PMN and address its corresponding mechanism of action. We found that pretreatment with PMN reduced reactive oxygen species production and DA neuron degeneration caused by exposure to 6-hydroxydopamine (6-OHDA), and therefore significantly improved the DA-mediated food-sensing behavior of 6-OHDA-exposed worms and prolonged their lifespan. PMN also diminished the accumulation of α-synuclein in transgenic worms and transfected cells. In our study of the mechanism of action, we found that PMN lessened ARTS-mediated degradation of X-linked inhibitor of apoptosis (XIAP) by enhancing the expression of PINK1/parkin. This led to reduced 6-OHDA-induced apoptosis, enhanced activity of the ubiquitin–proteasome system, and increased autophagy, which diminished the accumulation of α-synuclein. The use of small interfering RNA to down-regulate parkin reversed the benefits of PMN in the PD models. Our findings suggest PMN as a candidate compound worthy of further evaluation for the treatment of PD.

scholarly journals Anticancer Effects of Green Tea and the Underlying Molecular Mechanisms in Bladder Cancer

Medicines ◽  
2018 ◽  
Vol 5 (3) ◽  
pp. 87 ◽  
Author(s):  
Yasuyoshi Miyata ◽  
Tomohiro ScienMatsuoces ◽  
Kyohei Araki ◽  
Yuichiro Nakamura ◽  
Yuji Sagara ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Green Tea ◽  
Molecular Mechanisms ◽  
Treatment Strategies ◽  
In Vitro Studies ◽  
Green Tea Polyphenols ◽  
Tea Consumption ◽  
Anticancer Effects

Green tea and green tea polyphenols (GTPs) are reported to inhibit carcinogenesis and malignant behavior in several diseases. Various in vivo and in vitro studies have shown that GTPs suppress the incidence and development of bladder cancer. However, at present, opinions concerning the anticancer effects and preventive role of green tea are conflicting. In addition, the detailed molecular mechanisms underlying the anticancer effects of green tea in bladder cancer remain unclear, as these effects are regulated by several cancer-related factors. A detailed understanding of the pathological roles and regulatory mechanisms at the molecular level is necessary for advancing treatment strategies based on green tea consumption for patients with bladder cancer. In this review, we discuss the anticancer effects of GTPs on the basis of data presented in in vitro studies in bladder cancer cell lines and in vivo studies using animal models, as well as new treatment strategies for patients with bladder cancer, based on green tea consumption. Finally, on the basis of the accumulated data and the main findings, we discuss the potential usefulness of green tea as an antibladder cancer agent and the future direction of green tea-based treatment strategies for these patients.

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