scholarly journals Anti-tumour Effect of Cyanidin-3-o-glucoside Combined With Cisplatin in the Mice Xenograft Models of Cervical Cancer

2021 ◽  
Author(s):  
Xu Li ◽  
Jingjing Mu ◽  
Xianjun Meng
Keyword(s):  
Cervical Cancer ◽  
First Line ◽  
Treatment Groups ◽  
Xenograft Models ◽  
Induced Apoptosis ◽  
Line Drug ◽  
Anti Tumour Effect ◽  
Mtor Signalling ◽  
Mtor Signalling Pathway

Abstract Cervical cancer is the fourth most common carcinoma in women. Cisplatin (DDP) is the first-line drug for the treatment of cervical cancer. Although efficacious, its application is constrained by the intolerance and serious adverse effects associated with cisplatin. Here, we aimed to investigate the in vivo anti-cervical cancer effects of cyanidin-3-o-glucoside (C3G), a type of anthocyanin, and DDP, when used alone or in combination; a BALB/c nude mouse xenograft tumour model was used. The tumour was inhibited in the three treatment groups when compared with untreated controls. The inhibition of tumour was 40.49%, 50.15%, and 58.49% when treated with C3G alone [40 mg/kg body weight (bw)], DDP alone (3 mg/kg bw), or a combination of C3G and DDP, respectively. Immunohistochemistry analysis indicated that treatment with C3G, DDP, or the combination induced apoptosis in xenograft tumours. Furthermore, after treatment, Bcl-2 level was decreased, Bax and cleaved caspase-3 expression was activated, and the PI3K/AKT/mTOR signalling pathway was modulated. These results suggest that the combination of C3G and DDP may have significant synergistic anti-tumour efficacy in patients; therefore, this combination therapy has great potential for the treatment of cervical cancer.

scholarly journals Long Noncoding RNA KCNMB2-AS1 Stabilized by N6-Methyladenosine Modification Promotes Cervical Cancer Growth Through Acting as a Competing Endogenous RNA

2020 ◽  
Vol 29 ◽  
pp. 096368972096438
Author(s):  
Yao Zhang ◽  
Dian Wang ◽  
Dan Wu ◽  
Donghong Zhang ◽  
Ming Sun
Keyword(s):  
Cervical Cancer ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Competing Endogenous Rna ◽  
Regulatory Circuit ◽  
Therapeutic Possibility ◽  
Xenograft Models ◽  
Poor Outcomes ◽  
Induced Apoptosis

Long noncoding RNA (lncRNA) is emerging as an essential regulator in the development and progression of cancer, including cervical cancer (CC). In this study, we found a CC-related lncRNA, KCNMB2-AS1, which was significantly overexpressed in CC and linked to poor outcomes. Depletion of KCNMB2-AS1 remarkably inhibited CC cell proliferation and induced apoptosis. In vivo xenograft models revealed that knockdown of KCNMB2-AS1 evidently delayed tumor growth. Mechanistically, KCNMB2-AS1 was predominantly located in the cytoplasm and served as a competing endogenous RNA to abundantly sponge miR-130b-5p and miR-4294, resulting in the upregulation of IGF2BP3, a well-documented oncogene in CC. Moreover, IGF2BP3 was able to bind KCNMB2-AS1 by three N6-methyladenosine (m6A) modification sites on KCNMB2-AS1, in which IGF2BP3 acted as an m6A “reader” and stabilized KCNMB2-AS1. Thus, KCNMB2-AS1 and IGF2BP3 formed a positive regulatory circuit that enlarged the tumorigenic effect of KCNMB2-AS1 in CC. Together, our data clearly suggest that KCNMB2-AS1 is a novel oncogenic m6A-modified lncRNA in CC, targeting KCNMB2-AS1 and its related molecules implicate the therapeutic possibility for CC patients.

scholarly journals The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy

Oncogene ◽  
2021 ◽  
Author(s):  
Jian Chen ◽  
Risi Na ◽  
Chao Xiao ◽  
Xiao Wang ◽  
Yupeng Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Patient Survival ◽  
Serine Hydroxymethyltransferase ◽  
First Line ◽  
Xenograft Models ◽  
Potential Opportunity ◽  
First Line Treatment ◽  
Novel Therapeutic

Abstract5-Fluorouracil (5-FU)-based chemotherapy is the first-line treatment for colorectal cancer (CRC) but is hampered by chemoresistance. Despite its impact on patient survival, the mechanism underlying chemoresistance against 5-FU remains poorly understood. Here, we identified serine hydroxymethyltransferase-2 (SHMT2) as a critical regulator of 5-FU chemoresistance in CRC. SHMT2 inhibits autophagy by binding cytosolic p53 instead of metabolism. SHMT2 prevents cytosolic p53 degradation by inhibiting the binding of p53 and HDM2. Under 5-FU treatment, SHMT2 depletion promotes autophagy and inhibits apoptosis. Autophagy inhibitors decrease low SHMT2-induced 5-FU resistance in vitro and in vivo. Finally, the lethality of 5-FU treatment to CRC cells was enhanced by treatment with the autophagy inhibitor chloroquine in patient-derived and CRC cell xenograft models. Taken together, our findings indicate that autophagy induced by low SHMT2 levels mediates 5-FU resistance in CRC. These results reveal the SHMT2–p53 interaction as a novel therapeutic target and provide a potential opportunity to reduce chemoresistance.

scholarly journals HDAC6 inhibitor WT161 performs antitumor effect on osteosarcoma and synergistically interacts with 5-FU

2021 ◽  
Author(s):  
Jun Sun ◽  
Wei Wu ◽  
Xiaofeng Tang ◽  
Feifei Zhang ◽  
Cheng Ju ◽  
...  
Keyword(s):  
Dependent Manner ◽  
Osteosarcoma Cells ◽  
Synergistic Inhibition ◽  
Proliferative Effect ◽  
Xenograft Models ◽  
Hdac6 Inhibitor ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

Background: WT161, as a selective HDAC6 inhibitor, has been shown to play anti-tumor effects on several kinds of cancers. The aim of this study is to explore the roles of WT161 in osteosarcoma and its underlying mechanisms. Methods: The anti-proliferative effect of WT161 on osteosarcoma cells was examined using MTT assay and colony formation assay. Cell apoptosis was analyzed using flow cytometer. The synergistic effect was evaluated by isobologram analysis using CompuSyn software. The osteosarcoma xenograft models were established to evaluate the anti-proliferative effect of WT161 in vivo. Results: WT161 suppressed the cell growth and induced apoptosis of osteosarcoma cells in a dose- and time-dependent manner. Mechanistically, we found that WT161 treatment obviously increased the protein level of PTEN and decreased the phosphorylation level of AKT. More importantly, WT161 show synergistic inhibition with 5-FU on osteosarcoma cells in vitro and in vivo. Conclusions: These results indicate that WT161 inhibits the growth of osteosarcoma through PTEN and has a synergistic efficiency with 5-FU.

scholarly journals HDAC6 Inhibitor WT161 Performs Antitumor Effect on Ostersarcoma and Synergistically Interacts with 5-FU

2020 ◽  
Author(s):  
Jun Sun ◽  
Xiaofeng Tang ◽  
Feifei Zhang ◽  
Cheng Ju ◽  
Renfeng Liu ◽  
...  
Keyword(s):  
Osteosarcoma Cell ◽  
Dependent Manner ◽  
Osteosarcoma Cells ◽  
Proliferative Effect ◽  
Xenograft Models ◽  
Hdac6 Inhibitor ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

Abstract Background: WT161 as a new selective HDAC6 inhibitor has been shown to play anti-tumor effects on multiple myeloma and breast cancer. However, the role of WT161 in osteosarcoma remains unclear. The aim of this study is to explore the role of WT161 in osteosarcoma and its underlying mechanisms.Methods: The anti-proliferative effect of WT161 on osteosarcoma cells was examined using MTT assay and colony formation assay. Cell apoptosis was analyzed using flow cytometer. The synergistic effect was evaluated by isobologram analysis using CompuSyn software. The osteosarcoma xenograft models were esatablished to evaluate the anti-proliferative effect of WT161 in vivo.Results: WT161 suppressed the cell growth and induced apoptosis of osteosarcoma cells in a dose- and time-dependent manner. Mechanistically, we found that WT161 treatment obviously increased the protein expression level of PTEN and decreased the phosphorylation level of AKT. Notably, WT161 shows synergistically inhibitory effects on osteosarcoma cell combined with 5-FU. Animal experiment results show WT161 inhibits the growth of osteosarcoma tumor and further illustrates that WT161 and 5-FU have a synergistic efficiency in osteosarcoma.Conclusions: These results indicate that WT161 inhibiting the growth of osteosarcoma through PTEN and has a synergistic efficiency with 5-FU.

scholarly journals DRES-07. TMZ-LEV- IFN COCKTAIL REGIMEN SIGNIFICANTLY INHIBITED THE GROWTH OF GLIOMA IN VIVO

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi72-vi73
Author(s):  
Xiang-rong Ni ◽  
Jing Wang ◽  
Fu-rong Chen ◽  
Hai-ping Cai ◽  
Yan-jiao Yu ◽  
...  
Keyword(s):  
Protein Expression ◽  
Tumor Growth ◽  
Tumor Volume ◽  
Control Group ◽  
First Line ◽  
Killing Effect ◽  
Treatment Groups ◽  
Mgmt Protein ◽  
Tumor Killing

Abstract OBJECTIVE Temozolomide (TMZ), is the first line chemotherapeutic drug for glioma. Previous studies have suggested that interferon (IFN) and levetiracetam (LEV) could respectively reverse the resistance of TMZ by down-regulating MGMT expression. This study, we aim to investigate the therapeutic effect of a cocktail chemotherapy regimen combining TMZ, LEV, IFN in vivo. METHODS Glioma cell lines U251 and SKMG-4 (MGMT protein expression positive), U138 and GSC-1(MGMT protein expression negative) were used for producing xenograft tumors. The xenograft tumors were established by subcutaneously injecting 1×106 glioma cells into female BALB/C nude mice and divided into 5 treatment groups: Control, TMZ, TMZ+IFN, TMZ+LEV, TMZ+LEV+IFN. The treatment with TMZ (50 mg/kg, i.p.), IFN (2×105 IU, s.c.), LEV (150 mg/kg, i.p.) once a day for five consecutive days and xenograft tumors were measured every two days. RESULTS We identified that U138, U251, SKMG-4 tumor growth among TMZ, TMZ+IFN, TMZ+LEV, TMZ+LEV+IFN were all significantly inhibited (P< 0.05), compared with the control. As for U251 and SKMG-4, tumor killing effect of all 4 treatment groups were not different (P > 0.05). In the treatment of mice bearing U138 glioma, the tumor weight of TMZ+LEV+IFN (0.2688±0.1169 g) group was the lowest and significantly lower than that of TMZ+LEV (0.6574±0.08174g, P=0.0261), TMZ+IFN(0.6108±0.07317 g, P=0.0381), and TMZ (0.9054±0.07154 g, P=0.0017) group. Glioma stem cells GSC-1 was highly resistant to TMZ, tumor volume of TMZ group was not different from control group (P >0.05). While compared with TMZ (1.993±0.1274 g) group, in TMZ+IFN (1.506±0.1223g, P=0.0203), TMZ+LEV (1.178±0.1807g, P=0.0042), and TMZ+LEV+IFN (1.049±0.2171 g, P=0.0038) groups, GSC-1 tumor growth were significantly inhibited(P< 0.05). CONCLUSION Our data demonstrate that both IFN and LEV can sensitize TMZ effect on glioma in vivo, even for MGMT(+) tumors, and TMZ-LEV-IFN cocktail regimen seems the best. Key words: glioma, TMZ, LEV, IFN

scholarly journals Inhibition of FGF2-Mediated Signaling in GIST—Promising Approach for Overcoming Resistance to Imatinib

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1674
Author(s):  
Sergei Boichuk ◽  
Aigul Galembikova ◽  
Ekaterina Mikheeva ◽  
Firuza Bikinieva ◽  
Aida Aukhadieva ◽  
...  
Keyword(s):  
Tumor Response ◽  
Molecular Target ◽  
Compensatory Mechanism ◽  
Dependent Manner ◽  
First Line ◽  
Induced Apoptosis ◽  
First Time ◽  
Malignant Behavior ◽  
First Line Treatment

Inhibition of KIT-signaling is a major molecular target for gastrointestinal stromal tumor (GIST) therapy, and imatinib mesylate (IM) is known as the most effective first-line treatment option for patients with advanced, unresectable, and/or metastatic GISTs. We show here for the first time that the inhibition of KIT-signaling in GISTs induces profound changes in the cellular secretome, leading to the release of multiple chemokines, including FGF-2. IM increased migration, invasion, and colony formation of IM-resistant GISTs in an FGF2-dependent manner, whereas the use of blocking anti-FGF2 antibodies or BGJ398, a selective FGFR inhibitor, abolished these effects, thus suggesting that the activation of FGF2-mediated signaling could serve as a compensatory mechanism of KIT-signaling inhibited in GISTs. Conversely, FGF-2 rescued the growth of IM-naive GISTs treated by IM and protected them from IM-induced apoptosis, consistent with the possible involvement of FGF-2 in tumor response to IM-based therapy. Indeed, increased FGF-2 levels in serum and tumor specimens were found in IM-treated mice bearing IM-resistant GIST xenografts, whereas BGJ398 used in combination with IM effectively inhibited their growth. Similarly, increased FGF-2 expression in tumor specimens from IM-treated patients revealed the activation of FGF2-signaling in GISTs in vivo. Collectively, the continuation of IM-based therapy for IM-resistant GISTs might facilitate disease progression by promoting the malignant behavior of tumors in an FGF2-dependent manner. This provides a rationale to evaluate the effectiveness of the inhibitors of FGF-signaling for IM-resistant GISTs.

scholarly journals Cytotoxic and Senolytic Effects of Methadone in Combination with Temozolomide in Glioblastoma Cells

2020 ◽  
Vol 21 (19) ◽  
pp. 7006
Author(s):  
Bernd Kaina ◽  
Lea Beltzig ◽  
Andrea Piee-Staffa ◽  
Bodo Haas
Keyword(s):  
Pain Treatment ◽  
Human Fibroblasts ◽  
Methadone Treatment ◽  
Fibroblast Cell ◽  
Glioblastoma Cells ◽  
First Line ◽  
Induced Apoptosis ◽  
Methadone Concentration

Methadone is an analgesic drug used for pain treatment and heroin substitution. Recently, methadone has been proposed to be useful also for cancer therapy, including glioblastoma multiforme (GBM), the most severe form of brain cancer, because experiments on cultured glioma cells treated with doxorubicin showed promising results. Doxorubicin, however, is not used first-line in GBM therapy. Therefore, we analyzed the cytotoxic effect of methadone alone and in combination with temozolomide, a DNA-alkylating drug that is first-line used in GBM treatment, utilizing GBM-derived cell lines and a human fibroblast cell line. We show that methadone is cytotoxic on its own, inducing apoptosis and necrosis, which was observed at a concentration above 20 µg/mL. Methadone was similar toxic in isogenic MGMT expressing and non-expressing cells, and in LN229 glioblastoma and VH10T human fibroblasts. The apoptosis-inducing activity of methadone is not bound on the opioid receptor (OR), since naloxone, a competitive inhibitor of OR, did not attenuate methadone-induced apoptosis/necrosis. Administrating methadone and temozolomide together, temozolomide had no impact on methadone-induced apoptosis (which occurred 3 days after treatment), while temozolomide-induced apoptosis (which occurred 5 days after treatment) was unaffected at low (non-toxic) methadone concentration (5 µg/mL), and at high (toxic) methadone concentration (20 µg/mL) the cytotoxic effects of methadone and temozolomide were additive. Methadone is not genotoxic, as revealed by comet and γH2AX assay, and did not ameliorate the genotoxic effect of temozolomide. Further, methadone did not induce cellular senescence and had no effect on temozolomide-induced senescence. Although methadone was toxic on senescent cells, it cannot be considered a senolytic drug since cytotoxicity was not specific for senescent cells. Finally, we show that methadone had no impact on the MGMT promoter methylation. Overall, the data show that methadone on glioblastoma cells in vitro is cytotoxic and induces apoptosis/necrosis at doses that are above the level that can be achieved in vivo. It is not genotoxic, and does not ameliorate the cell killing or the senescence-inducing effect of temozolomide (no synergistic effect), indicating it has no impact on temozolomide-induced signaling pathways. The data do not support the notion that concomitant methadone treatment supports temozolomide-based chemotherapy.

scholarly journals Cucurbitacin E inhibits osteosarcoma cells proliferation and invasion through attenuation of PI3K/AKT/mTOR signalling pathway

2016 ◽  
Vol 36 (6) ◽  
Author(s):  
Ying Wang ◽  
Shumei Xu ◽  
Yaochi Wu ◽  
Junfeng Zhang
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Signalling Pathway ◽  
Cell Counting ◽  
Cell Cycle Distribution ◽  
Mesenchymal Transition ◽  
Cucurbitacin E ◽  
Mtor Signalling ◽  
Mtor Signalling Pathway

Cucurbitacin E (CuE), a potent member of triterpenoid family isolated from plants, has been confirmed as an antitumour agent by inhibiting proliferation, migration and metastasis in diverse cancer. However, the effects and mechanisms of CuE on osteosarcoma (OS) have not been well understood. The present study aimed to test whether CuE could inhibit growth and invasion of OS cells and reveal its underlying molecular mechanism. After various concentrations of CuE treatment, the anti-proliferative effect of CuE was assessed using the cell counting Kit-8 assay. Flow cytometry analysis was employed to measure apoptosis of OS cells. Cell cycle distribution was analysed by propidium iodide staining. Transwell assay was performed to evaluate the effect of CuE on invasion potential of OS cells. The protein levels were measured by western blot. In addition, the potency of CuE on OS cells growth inhibition was assessed in vivo. Our results showed that CuE inhibited cell growth and invasion, induced a cell cycle arrest and triggered apoptosis and modulated the expression of cell growth, cell cycle and cell apoptosis regulators. Moreover, CuE inhibited the PI3K/Akt/mTOR pathway and epithelial–mesenchymal transition (EMT), which suppressed the invasion and metastasis of OS. In addition, we also found that CuE inhibited OS cell growth in vivo. Taken together, our study demonstrated that CuE could inhibit OS tumour growth and invasion through inhibiting the PI3K/Akt/mTOR signalling pathway. Our findings suggest that CuE can be considered to be a promising anti-cancer agent for OS.

scholarly journals Evaluation of Novel 3-Hydroxyflavone Analogues as HDAC Inhibitors against Colorectal Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Subhankar Biswas ◽  
Neetinkumar D. Reddy ◽  
B. S. Jayashree ◽  
C. Mallikarjuna Rao
Keyword(s):  
Colorectal Cancer ◽  
Caspase 3 ◽  
Hdac Inhibitors ◽  
Annexin V ◽  
Aberrant Crypt Foci ◽  
Treatment Groups ◽  
Activation Assay ◽  
Induced Apoptosis ◽  
Hct116 Cells

Alteration of epigenetic enzymes is associated with the pathophysiology of colon cancer with an overexpression of histone deacetylase 8 (HDAC8) enzyme in this tissue. Numerous reports suggest that targeting HDAC8 is a viable strategy for developing new anticancer drugs. Flavonols provide a rich source of molecules that are effective against cancer; however, their clinical use is limited. The present study investigated the potential of quercetin and synthetic 3-hydroxyflavone analogues to inhibit HDAC8 enzyme and evaluated their anticancer property. Synthesis of the analogues was carried out, and cytotoxicity was determined using MTT assay. Nonspecific and specific HDAC enzyme inhibition assays were performed followed by the expression studies of target proteins. Induction of apoptosis was studied through annexin V and caspase 3/7 activation assay. Furthermore, the analogues were assessed against in vivo colorectal cancer. Among the synthesized analogues, QMJ-2 and QMJ-5 were cytotoxic against HCT116 cells with an IC50 value of 68 ± 2.3 and 27.4 ± 1.8 µM, respectively. They inhibited HDAC enzyme in HCT116 cells at an IC50 value of 181.7 ± 22.04 and 70.2 ± 4.3 µM, respectively, and inhibited human HDAC8 and 1 enzyme at an IC50 value of <50 µM with QMJ-5 having greater specificity towards HDAC8. A reduction in the expression of HDAC8 and an increase in acetyl H3K9 expression were observed with the synthesized analogues. Both QMJ-2 and QMJ-5 treatment induced apoptosis through the activation of caspase 3/7 evident from 55.70% and 83.55% apoptotic cells, respectively. In vivo studies revealed a significant decrease in colon weight to length ratio in QMJ-2 and QMJ-5 treatment groups compared to DMH control. Furthermore, a reduction in aberrant crypt foci formation was observed in the treatment groups. The present study demonstrated the potential of novel 3-hydroxyflavone analogues as HDAC8 inhibitors with anticancer property against colorectal cancer.

scholarly journals Properly Substituted Cyclic Bis-(2-bromobenzylidene) Compounds Behaved as Dual p300/CARM1 Inhibitors and Induced Apoptosis in Cancer Cells

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3122
Author(s):  
Rossella Fioravanti ◽  
Stefano Tomassi ◽  
Elisabetta Di Bello ◽  
Annalisa Romanelli ◽  
Andrea Maria Plateroti ◽  
...  
Keyword(s):  
Leukemia Cell ◽  
Selective Inhibition ◽  
Cellular Assays ◽  
Leukemia Cell Lines ◽  
Xenograft Models ◽  
Multiple Ligands ◽  
Induced Apoptosis ◽  
Cyclic Compounds ◽  
Mcf 7

Bis-(3-bromo-4-hydroxy)benzylidene cyclic compounds have been reported by us as epigenetic multiple ligands, but different substitutions at the two wings provided analogues with selective inhibition. Since the 1-benzyl-3,5-bis((E)-3-bromobenzylidene)piperidin-4-one 3 displayed dual p300/EZH2 inhibition joined to cancer-selective cell death in a panel of tumor cells and in in vivo xenograft models, we prepared a series of bis((E)-2-bromobenzylidene) cyclic compounds 4a–n to test in biochemical (p300, PCAF, SIRT1/2, EZH2, and CARM1) and cellular (NB4, U937, MCF-7, SH-SY5Y) assays. The majority of 4a–n exhibited potent dual p300 and CARM1 inhibition, sometimes reaching the submicromolar level, and induction of apoptosis mainly in the tested leukemia cell lines. The most effective compounds in both enzyme and cellular assays carried a 4-piperidone moiety and a methyl (4d), benzyl (4e), or acyl (4k–m) substituent at N1 position. Elongation of the benzyl portion to 2-phenylethyl (4f) and 3-phenylpropyl (4g) decreased the potency of compounds at both the enzymatic and cellular levels, but the activity was promptly restored by introduction of a ketone group into the phenylalkyl substituent (4h–j). Western blot analyses performed in NB4 and MCF-7 cells on selected compounds confirmed their inhibition of p300 and CARM1 through decrease of the levels of acetyl-H3 and acetyl-H4, marks for p300 inhibition, and of H3R17me2, mark for CARM1 inhibition.

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