Antitumor effects of the small molecule DMAMCL in neuroblastoma via suppressing aerobic glycolysis and targeting PFKL

Abstract Background Neuroblastoma (NB) is a common solid malignancy in children that is associated with a poor prognosis. Although the novel small molecular compound Dimethylaminomicheliolide (DMAMCL) has been shown to induce cell death in some tumors, little is known about its role in NB. Methods We examined the effect of DMAMCL on four NB cell lines (NPG, AS, KCNR, BE2). Cellular confluence, survival, apoptosis, and glycolysis were detected using Incucyte ZOOM, CCK-8 assays, Annexin V-PE/7-AAD flow cytometry, and Seahorse XFe96, respectively. Synergistic effects between agents were evaluated using CompuSyn and the effect of DMAMCL in vivo was evaluated using a xenograft mouse model. Phosphofructokinase-1, liver type (PFKL) expression was up- and down-regulated using overexpression plasmids or siRNA. Results When administered as a single agent, DMAMCL decreased cell proliferation in a time- and dose-dependent manner, increased the percentage of cells in SubG1 phase, and induced apoptosis in vitro, as well as inhibiting tumor growth and prolonging survival in tumor-bearing mice (NGP, BE2) in vivo. In addition, DMAMCL exerted synergistic effects when combined with etoposide or cisplatin in vitro and displayed increased antitumor effects when combined with etoposide in vivo compared to either agent alone. Mechanistically, DMAMCL suppressed aerobic glycolysis by decreasing glucose consumption, lactate excretion, and ATP production, as well as reducing the expression of PFKL, a key glycolysis enzyme, in vitro and in vivo. Furthermore, PFKL overexpression attenuated DMAMCL-induced cell death, whereas PFKL silencing promoted NB cell death. Conclusions The results of this study suggest that DMAMCL exerts antitumor effects on NB both in vitro and in vivo by suppressing aerobic glycolysis and that PFKL could be a potential target of DMAMCL in NB.

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TB-4 Antitumor effects of a novel curcumin derivative curcumin monoglucuronide on glioblastoma cells in vitro and in vivo

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab159.022 ◽

2021 ◽

Vol 3 (Supplement_6) ◽

pp. vi6-vi6

Author(s):

Takashi Fujii ◽

Shun Yamamuro ◽

Masamichi Takahashi ◽

Akihide Kondo ◽

Yoshitaka Narita ◽

...

Keyword(s):

Cell Death ◽

Water Soluble ◽

Dependent Manner ◽

Antitumor Effects ◽

Multiple Cell ◽

Human Gbm ◽

Dose Dependent ◽

Novel Therapeutic

Abstract The therapeutic outcome of glioblastomas (GBMs) is still very poor. Therefore, invention of novel therapeutic methods against GBM cases is considered urgent. The antitumor effects of naturally-derived compounds are attracting attention recently, and therapeutic efficacy of curcumin, a plant-derived compound previously used for multiple purpose, has been indicated in many cancer systems; however, clinical application of curcumin is considered difficult because of its poor bioavailability (under 1 %). Curcumin monoglucuronide (CMG), a water-soluble prodrug of curcumin recently developed for overcoming this weakness, has been demonstrated excellent antitumor effects for several malignancies in vitro and in vivo; therefore, we investigated the effects of CMG against GBM cells. CMG induced cell death of human GBM cells lines (T98G, U251MG, and U87MG) by dose dependent manner by triggering multiple forms of cell death such as apoptosis and perthanatos. Immunoblotting of CMG-treated GBM cell lysates demonstrated activation of multiple cell death signaling. Furthermore, immunodeficiency mice harboring intracerebral U87MG cell xenografts systemically treated by CMG showed significantly prolonged survival compared with control mice. These results suggest CMG would be a novel therapeutic agent against GBM cases.

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Synergistic Effects of a Novel Water-Soluble Small Molecule, ON 013105, and Rituximab on Mantle Cell Lymphoma In Vitro and In Vivo

Blood ◽

10.1182/blood.v116.21.771.771 ◽

2010 ◽

Vol 116 (21) ◽

pp. 771-771

Author(s):

Anil Prasad ◽

Ashutosh Shrivastava ◽

Ramana Reddy ◽

Amanda M. Gillum ◽

E. Premkumar Reddy ◽

...

Keyword(s):

Cell Death ◽

Tumor Volume ◽

Cell Lymphoma ◽

Single Agent ◽

Dependent Manner ◽

Mantle Cell ◽

Dose Dependent ◽

Efficacy Studies

Abstract Abstract 771 Mantle cell lymphoma (MCL) is a well-defined subtype of B-cell non-Hodgkin's lymphoma characterized by a t(11;14)(q13;q32) chromosomal translocation, and associated with constitutive over-expression of cyclin D1. MCL generally has poor clinical outcome marked by relapse. There is considerable need for novel and more effective agents against MCL. ON 013105 belongs to the styryl benzylsulfones, a novel family of non-ATP competitive kinase inhibitors with potent antitumor activity. Here, we report that ON 013105 induced cell death in a dose-dependent manner in two well-characterized MCL cell lines, Granta 519 and Z138C. In vitro cell death was preceded by the activation of caspases 3 and 9 and cleavage of PARP, indicating induction of apoptosis. In addition, ON 013105-treated cells exhibited reduced expression of cyclin D1 and c-myc. These effects on expression and apoptosis were not evident in cells treated with ON 013101, an inactive (non-cytotoxic) isomer of ON 013105. Since it is common clinical practice to combine Rituximab (RTX) with chemotherapy regimens in treating CD20+ B cell-lymphoma, we studied ON 013105 combined with rituximab, and found ON 013105-induced apoptosis more efficiently than when employed as a single agent. The combination effect on cell death was synergistic in nature. To further study this activity, we focused on Mcl-1, a member of the anti-apoptotic Bcl-2 family known to inhibit apoptosis induced by cytotoxic stimuli through antagonizing pro-apoptotic Bcl-2 family members. We observed a dramatic decrease in Mcl-1 expression in cells treated with ON 013105 (but not with ON 013101) in combination with RTX, compared to ON 013105 alone. We also evaluated the effects of ON 013105 in combination with Doxorubicin or Vincristine and found that both these compounds also significantly enhanced the cytotoxic effects of ON 013105. In vivo pharmacokinetics studies in a mouse model system revealed that plasma concentrations up to 50 μM could be safely achieved by administering ON 013105 at 100 mg/kg via i.v or i.p routes. Significant levels of ON 013100 (30-40% of the peak levels of ON 013105), an active metabolite, were also detected in the circulation, presumably due to the in vivo dephosphorylation of ON 013105 by phosphatase action. ON 013105 was well tolerated in mice, both as a single agent and when used in combination with rituximab, and there were no systemic toxic effects to the host and no loss in body weight. In vivo efficacy studies in mouse xenograft models employing transplanted MCL cells demonstrated that ON 013105 effectively inhibited tumor growth in a dose-dependent manner. ON 013015 at 25 mg/kg (Q2D) and 75mg/kg (Q7D) induced 46% and 80 % reduction of tumor volume, respectively, compared to controls, over 4 weeks of treatment. Moreover, ON 013105 at 25 mg/kg (Q2D) in a combination regimen with RTX (2.5 mg/kg, Q3D) induced over 85% reduction of tumor volume. Though in vivo efficacy studies of ON013015 (25 mg/kg, Q2D) in combination with Doxorubicin (3.5mg/kg, Q7D) or Vincristine (0.3mg/kg, Q2D) showed drastic decrease in tumor growth in mouse models, this effect was accompanied by severe side effects to the host, including mortality. In sum, ON 013105, alone and in combination with RTX may be a potent therapeutic agent against MCL. A Phase I dose escalation trial of ON 013105 as a single agent is underway in patients with relapsed/refractory lymphoma including MCL. Disclosures: No relevant conflicts of interest to declare.

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In Vitro and In Vivo Efficacy of a Novel Orally Bioavailable Beta-Catenin Inhibitor-BC2059- As Monotherapy or in Combination with Proteasome Inhibitors in Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.1816.1816 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1816-1816

Author(s):

Ioanna Savvidou ◽

Tiffany T. Khong ◽

Stephen K. Horrigan ◽

Andrew Spencer

Keyword(s):

Multiple Myeloma ◽

Cell Death ◽

Single Agent ◽

Proteasome Inhibitors ◽

Canonical Pathway ◽

Beta Catenin ◽

Dependent Manner ◽

Canonical Wnt

Abstract Background: The currently available treatment options are unlikely to be curative for the majority of Multiple Myeloma (MM) patients, emphasizing a continuing role for the introduction of investigational agents that overcome drug resistance. The canonical Wnt/β-catenin signalling pathway has been found to be dysregulated in MM, and its activation is associated with advanced stage MM, providing a rationale to evaluate the novel β-catenin inhibitor BC2059 in mono- and combination therapy with proteasome inhibitors in vitro and in vivo. Methods and Results: We evaluated the activation status of the canonical Wnt pathway in 12 genetically heterogeneous Human Myeloma Cell Lines (HMCL) by assessing the expression of β-catenin protein in the nuclear compartment (active form). This showed that nuclear β-catenin was present in all HMCL tested and absent in plasma cells derived from a healthy donor. Moreover, additional stimulation of the canonical pathway with rhWnt3a was shown to be pro-proliferative, in contrast, no proliferation was seen with activation of the non canonical pathway following treatment with rhWnt5a. BC2059 (50nM to 500nM) induced apoptosis of all 12 HMCL and was able to inhibit the proliferation of all HMCL tested in a dose and time dependent manner assessed by MTS assay and viable enumeration with trypan blue (IC50: 53nM to 247nM). Mimicking the bone marrow (BM) microenvironment by co-culturing HMCL with the immortalised human stromal cell line HS-5, BC2059 was able to overcome the protective effect of HS-5 (for example KMS18 at IC90=220nM had no stromal pro-survival effect). Similarly, BC2059 was able to abolish the pro-proliferative effect of rh-Wnt3a or conditioned media derived from MM patients' BM when used at doses >100nM or 50nM, respectively. BC2059 facilitated the degradation of β-catenin protein in the nuclear cellular compartment ( >50% decrease of nuclear β-catenin in KMS18 treated with 1.5xIC50 when compared with untreated cells), furthermore, using a reporter assay we showed that BC2059 inhibited TCF/LEF transcriptional activity in a dose-dependent manner and decreased the transcription of axin2, a down-stream target gene of β-catenin - 78% reduction in KMS18 cells treated with 1.5x IC50 when compared to untreated controls. BC2059-induced HMCL cell death was associated with activation of both the intrinsic and extrinsic caspase-dependent apoptotic pathways, as shown by the accumulation of the activated forms of caspases 8, 9 and 3 following BC2059 treatment. However, inhibition of the caspase-pathway by the addition of caspase inhibitors (pan-caspase inhibitor Z-VAD, and caspase-3 inhibitor Z-DEVD) could not abolish the pro-necrotic effect of BC2059 or BC2059 plus bortezomib, suggesting a possible role for autophagy-induced cell death. As β-catenin undergoes proteasome-mediated destruction and has been found to increase following bortezomib treatment, we evaluated the effect of combining BC2059 with Bortezomib. The combination was synergistic for 6/8 HMCL tested (e.g. for LP1 CI:0.64-0.55, where CI<1.1=synergism). We also evaluated the effect of the combination of BC2059 with next generation proteasome inhibitors (carfilzomib and marizomib) where it was shown to have synergistic and/or additive effects (e.g. for carfilzomib LP1 CI:0.33-0.99). Single agent BC2059 effectively killed primary MM tumour cells from relapsed/refractory MM patients (n=13) and the combination with bortezomib was synergistic (n=2) with no effect on healthy peripheral blood mononuclear cells (n=4). Finally, BC2059 (10mg/kg) prolonged survival of xenografted NSG mice compared to untreated controls with no major side effects in Wnt/β-catenin dependent tissues (GI track and haematopoiesis). Conclusion: We have demonstrated that BC2059 at nano-molar concentrations has a strong anti-MM effect both in vitro and in vivo and synergises with proteasome inhibitors. These data strongly support the clinical evaluation of BC2059 for the treatment of MM. Disclosures Horrigan: BetaCat Pharmaceuticals: Employment.

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Influence of icariin on inflammation, apoptosis, invasion, and tumor immunity in cervical cancer by reducing the TLR4/MyD88/NF-κB and Wnt/β-catenin pathways

Cancer Cell International ◽

10.1186/s12935-021-01910-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Chunyang Li ◽

Shuangqing Yang ◽

Huaqing Ma ◽

Mengjia Ruan ◽

Luyan Fang ◽

...

Keyword(s):

Cervical Cancer ◽

Underlying Mechanism ◽

Tissue Growth ◽

Migration And Invasion ◽

Dependent Manner ◽

Antitumor Effects ◽

Siha Cells ◽

Cervical Cancer Cells

Abstract Background Cervical cancer is a type of the most common gynecology tumor in women of the whole world. Accumulating data have shown that icariin (ICA), a natural compound, has anti-cancer activity in different cancers, including cervical cancer. The study aimed to reveal the antitumor effects and the possible underlying mechanism of ICA in U14 tumor-bearing mice and SiHa cells. Methods The antitumor effects of ICA were investigated in vivo and in vitro. The expression of TLR4/MyD88/NF-κB and Wnt/β-catenin signaling pathways were evaluated. Results We found that ICA significantly suppressed tumor tissue growth and SiHa cells viability in a dose-dependent manner. Also, ICA enhanced the anti-tumor humoral immunity in vivo. Moreover, ICA significantly improved the composition of the microbiota in mice models. Additionally, the results clarified that ICA significantly inhibited the migration, invasion capacity, and expression levels of TGF-β1, TNF-α, IL-6, IL-17A, IL-10 in SiHa cells. Meanwhile, ICA was revealed to promote the apoptosis of cervical cancer cells by down-regulating Ki67, survivin, Bcl-2, c-Myc, and up-regulating P16, P53, Bax levels in vivo and in vitro. For the part of mechanism exploration, we showed that ICA inhibits the inflammation, proliferation, migration, and invasion, as well as promotes apoptosis and immunity in cervical cancer through impairment of TLR4/MyD88/NF-κB and Wnt/β-catenin pathways. Conclusions Taken together, ICA could be a potential supplementary agent for cervical cancer treatment.

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Tumor cytotoxicity and immunogenicity of a novel V-jet neon plasma source compared to the kINPen

Scientific Reports ◽

10.1038/s41598-020-80512-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lea Miebach ◽

Eric Freund ◽

Stefan Horn ◽

Felix Niessner ◽

Sanjeev Kumar Sagwal ◽

...

Keyword(s):

Cell Death ◽

Dendritic Cells ◽

Cancer Cells ◽

Treatment Time ◽

Plasma Source ◽

In Vivo Model ◽

Antitumor Effects ◽

Plasma Device

AbstractRecent research indicated the potential of cold physical plasma in cancer therapy. The plethora of plasma-derived reactive oxygen and nitrogen species (ROS/RNS) mediate diverse antitumor effects after eliciting oxidative stress in cancer cells. We aimed at exploiting this principle using a newly designed dual-jet neon plasma source (Vjet) to treat colorectal cancer cells. A treatment time-dependent ROS/RNS generation induced oxidation, growth retardation, and cell death within 3D tumor spheroids were found. In TUM-CAM, a semi in vivo model, the Vjet markedly reduced vascularized tumors' growth, but an increase of tumor cell immunogenicity or uptake by dendritic cells was not observed. By comparison, the argon-driven single jet kINPen, known to mediate anticancer effects in vitro, in vivo, and in patients, generated less ROS/RNS and terminal cell death in spheroids. In the TUM-CAM model, however, the kINPen was equivalently effective and induced a stronger expression of immunogenic cancer cell death (ICD) markers, leading to increased phagocytosis of kINPen but not Vjet plasma-treated tumor cells by dendritic cells. Moreover, the Vjet was characterized according to the requirements of the DIN-SPEC 91315. Our results highlight the plasma device-specific action on cancer cells for evaluating optimal discharges for plasma cancer treatment.

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Pyrrolizidine Alkaloids Induce Cell Death in Human HepaRG Cells in a Structure-Dependent Manner

International Journal of Molecular Sciences ◽

10.3390/ijms22010202 ◽

2020 ◽

Vol 22 (1) ◽

pp. 202

Author(s):

Josephin Glück ◽

Julia Waizenegger ◽

Albert Braeuning ◽

Stefanie Hessel-Pras

Keyword(s):

Cell Death ◽

Cell Viability ◽

Pyrrolizidine Alkaloids ◽

Defense Mechanism ◽

Hepatoma Cell ◽

Hepatoma Cell Line ◽

Dependent Manner ◽

Human Hepatoma Cell

Pyrrolizidine alkaloids (PAs) are a group of secondary metabolites produced in various plant species as a defense mechanism against herbivores. PAs consist of a necine base, which is esterified with one or two necine acids. Humans are exposed to PAs by consumption of contaminated food. PA intoxication in humans causes acute and chronic hepatotoxicity. It is considered that enzymatic PA toxification in hepatocytes is structure-dependent. In this study, we aimed to elucidate the induction of PA-induced cell death associated with apoptosis activation. Therefore, 22 structurally different PAs were analyzed concerning the disturbance of cell viability in the metabolically competent human hepatoma cell line HepaRG. The chosen PAs represent the main necine base structures and the different esterification types. Open-chained and cyclic heliotridine- and retronecine-type diesters induced strong cytotoxic effects, while treatment of HepaRG with monoesters did not affect cell viability. For more detailed investigation of apoptosis induction, comprising caspase activation and gene expression analysis, 14 PA representatives were selected. The proapoptotic effects were in line with the potency observed in cell viability studies. In vitro data point towards a strong structure–activity relationship whose effectiveness needs to be investigated in vivo and can then be the basis for a structure-associated risk assessment.

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Ferroptosis contributes to isoflurane-induced neurotoxicity and learning and memory impairment

Cell Death Discovery ◽

10.1038/s41420-021-00454-8 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Pengfei Liu ◽

Jing Yuan ◽

Yetong Feng ◽

Xin Chen ◽

Guangsuo Wang ◽

...

Keyword(s):

Cell Death ◽

Learning And Memory ◽

Memory Impairment ◽

Close Association ◽

Dimethyl Fumarate ◽

Dependent Manner ◽

Transport Chain ◽

The Relationship

AbstractFerroptosis is a novel type of programmed cell death, which is different from apoptosis and autophagic cell death. Recently, ferroptosis has been indicated to contribute to the in vitro neurotoxicity induced by isoflurane, which is one of the most common anesthetics in clinic. However, the in vivo position of ferroptosis in isoflurane-induced neurotoxicity as well as learning and memory impairment remains unclear. In this study, we mainly explored the relationship between ferroptosis and isoflurane-induced learning and memory, as well as the therapeutic methods in mouse model. Our results indicated that isoflurane induced the ferroptosis in a dose-dependent and time-dependent manner in hippocampus, the organ related with learning and memory ability. In addition, the activity of cytochrome c oxidase/Complex IV in mitochondrial electron transport chain (ETC) was increased by isoflurane, which might further contributed to cysteine deprivation-induced ferroptosis caused by isoflurane exposure. More importantly, isoflurane-induced ferroptosis could be rescued by both ferroptosis inhibitor (ferrostatin-1) and mitochondria activator (dimethyl fumarate), which also showed effective therapeutic action against isoflurane-induced learning and memory impairment. Taken together, our data indicate the close association among ferroptosis, mitochondria and isoflurane, and provide a novel insight into the therapy mode against isoflurane-induced learning and memory impairment.

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

10.21203/rs.3.rs-691658/v1 ◽

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.

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Curcumol inhibits malignant biological behaviors and TMZ-resistance of glioma cells via reducing long noncoding RNA FoxD2-As1 promoted EZH2 activation

10.21203/rs.3.rs-415245/v1 ◽

2021 ◽

Author(s):

Xuyang Lv ◽

Jiangchuan Sun ◽

Linfeng Hu ◽

Ying Qian ◽

Chunlei Fan ◽

...

Keyword(s):

Cell Proliferation ◽

Noncoding Rna ◽

Glioma Cell ◽

Glioma Cells ◽

Migration And Invasion ◽

Dependent Manner ◽

Antitumor Effects ◽

Self Renewal

Abstract Background: Although curcumol has been shown to possess antitumor effects in several cancers, its effects on glioma are largely unknown. Recently, lncRNAs have been reported to play an oncogenic role through epigenetic modifications. Therefore, here, we investigated whether curcumol inhibited glioma progression by reducing FOXD2-AS1-mediated enhancer of zeste homolog 2 (EZH2) activation.Methods: MTT, colony formation, flow cytometry, Transwell, and neurosphere formation assays were used to assess cell proliferation, cell cycle, apoptosis, the percentage of CD133+ cells, the migration and invasion abilities, and the self-renewal ability. qRT-PCR, western blotting, immunofluorescence, and immunohistochemical staining were used to detect mRNA and protein levels. Isobologram analysis and methylation-specific PCR were used to analyze the effects of curcumol on TMZ resistance in glioma cells. DNA pull-down and Chip assays were employed to explore the molecular mechanism underlying the functions of curcumol in glioma cells. Tumorigenicity was determined using a xenograft formation assay. Results: Curcumol inhibited the proliferation, metastasis, self-renewal ability, and TMZ resistance of glioma cells in vitro and in vivo. FOXD2-AS1 was highly expressed in glioma cell lines, and its expression was suppressed by curcumol treatment in a dose- and time-dependent manner. The forced expression of FOXD2-AS1 abrogated the effect of curcumol on glioma cell proliferation, metastasis, self-renewal ability, and TMZ resistance. Moreover, the forced expression of FOXD2-AS1 reversed the inhibitory effect of curcumol on EZH2 activation.Conclusions: We showed for the first time that curcumol is effective in inhibiting malignant biological behaviors and TMZ-resistance of glioma cells by suppressing FOXD2-AS1-mediated EZH2 activation on anti-oncogenes. Our findings offer the possibility of exploiting curcumol as a promising therapeutic agent for glioma treatment and may provide an option for the clinical application of this natural herbal medicine.

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Nano-encapsulated tryptanthrin derivative for combined anticancer therapy via inhibiting indoleamine 2,3-dioxygenase and inducing immunogenic cell death

Nanomedicine ◽

10.2217/nnm-2019-0074 ◽

2019 ◽

Vol 14 (18) ◽

pp. 2423-2440 ◽

Cited By ~ 1

Author(s):

Canyu Yang ◽

Bing He ◽

Qiang Zheng ◽

Dakuan Wang ◽

Mengmeng Qin ◽

...

Keyword(s):

Cell Death ◽

Single Agent ◽

Tumor Burden ◽

Antitumor Efficacy ◽

In Vivo Studies ◽

Immunogenic Cell Death ◽

Indoleamine 2,3 Dioxygenase ◽

Tumor Tissues

Aim: We developed a polycaprolactone-based nanoparticle (NP) to encapsulate tryptanthrin derivative CY-1-4 and evaluated its antitumor efficacy. Materials & methods: CY-1-4 NPs were prepared and evaluated for their cytotoxicity and associated mechanisms, indoleamine 2,3-dioxygenase (IDO)-inhibitory ability, immunogenic cell death (ICD)-inducing ability and antitumor efficacy. Results: CY-1-4 NPs were 123 nm in size. In vitro experiments indicated that they could both induce ICD and inhibit IDO. In vivo studies indicated that a medium dose reduced 58% of the tumor burden in a B16-F10-bearing mouse model, decreased IDO expression in tumor tissues and regulated lymphocytes subsets in spleen and tumors. Conclusion: CY-1-4 is a potential antitumor candidate that could act as a single agent with combined functions of IDO inhibition and ICD induction.

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