scholarly journals Cancer-specific overmethylation of histone H3 lysines is necessary for methionine addiction and malignancy

2020 ◽  
Author(s):  
Jun Yamamoto ◽  
Sachiko Inubushi ◽  
Qinghong Han ◽  
Yoshihiko Tashiro ◽  
Yu Sun ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Therapeutic Target ◽  
Methylation Status ◽  
Histone H3 ◽  
Cell Types ◽  
Lysine Methylation ◽  
Normal Cells ◽  
Molecular Changes

AbstractMethionine addiction is a fundamental and general hallmark of cancer. Methionine addiction results from the overuse of methionine by cancer cells for excess transmethylation reactions. In order to identify excess transmethylation reactions in cancer, we compared the histone H3 lysine methylation status between methionine-addicted cancer cells, normal cells and revertants of methionine-addicted cancer cells which regained methionine independence and lost malignancy. The levels of H3K4me3, H3K9me3 and pan-methyl lysine of histone H3 were elevated in methionine-addicted cancer cells in vitro compared to methionine-independent revertants isolated from the cancer cells and to normal cells. Tumorigenicity in nude mice was highly reduced in the methionine-independent revertants compared to the parental cells. The methionine-independent revertants no longer overmethylated pan-methyl lysine of H3, H3K4me3 and H3K9me3. Our previous studies showed that methionine restriction (MR) selectively arrests methionine-addicted cancer cells due to loss of histone H3 lysine methylation, which was stable in normal cells under MR. Our previous and present results suggest that overmethylation of histone H3 lysine is necessary for methionine addiction of cancer, required for the growth of cancer cells in vitro and in vivo, and necessary for malignancy. Methionine addiction has revealed fundamental molecular changes necessary for malignancy and presents great potential as a pan-cancer therapeutic target.Signiificance StatementAll cancer cell types are methionine-addicted. Methionine addiction is due to the overuse of methionine by cancer cells for excess transmethylation reactions. In the present study, we showed that the level of histone H3 lysine methylation was elevated in methionine-addicted cancer cells compared to normal fibroblasts and methionine-independent revertants with reduced malignancy that were derived from the methionine-addicted cancer cells. These results suggest that overmethylation of histone H3 lysine is necessary for methionine addiction of cancer and malignancy itself. Methionine addiction has revealed fundamental molecular changes necessary for malignancy and has been shown to be a universal therapeutic target in numerous pre-clinical studies of all major cancer types and has great clinical potential.

Innovative dual system for selective eradication of cancer cells using exosomes carrying natural bacterial toxin-antitoxin (TA).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14635-e14635
Author(s):  
Shiran Shapira ◽  
Ilana Boustanai ◽  
Dina Kazanov ◽  
Ahmad Fokra ◽  
Ezra Bernstein ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Xenograft Model ◽  
Genetic Alterations ◽  
Bacterial Toxin ◽  
Genetic Profile ◽  
Dependent Manner ◽  
Normal Cells ◽  
Responsive Element

e14635 Background: Inactivation of P53 and activation of ras are frequent genetic alterations in cancer. We have shown in vitro and in vivo, that the TA system can selectively and effectively eradicate RAS-mutated cancer cells. Aim: Selective killing of cancer cells while sparing the normal cells based on tumor genetic signature. Methods: A “first generation” ΔE1/ΔE3 human type-5 adenoviral-vectors for gene delivery were designed and constructed to specifically target cancer cells. They are designated as "PY4-mazF-mCherry" (PY4, ras responsive element), "ΔPY4-mazF-mCherry" (control viruses) and "RGC-mazE-IRES-GFP" (RGC, P53 responsive element). Their potency was tested in vitro, by the enzymatic MTT assay, microscopic observation, colony formation assay and FACS analysis, and in a xenograft model of CRC. Next, we generated, small natural vesicles, exosomes, that directly targeted cancer through specific small antibody fragments against CD24 that is expressed in most cancer cells and rarely on normal cells. Results: The TA system ("PY4-mazF-mCherry"+"RGC-mazE-IRES-GFP") induced a massive cell death, in a dose-dependent manner in vitro, 69% as compared to 19% in control co-infected ("ΔPY4-mazF-mCherry"+"RGC-mazE-IRES-GFP") HCT116 CRC cells (mutated RAS and p53). In vivo, growth of HCT116-/- ( KRASmutand P53mut) and HCT116+/+ ( KRASmut and P53wt) tumors were significantly inhibited (70% and 65%, respectively). Conclusions: 1. Abusing the P53 genetic status and the activated Ras pathway holds promising effective and safe strategy to target tumor cells while sparing normal tissues. 2. It is a proof of concept for personalized cancer therapy based on the tumor genetic profile.

Cancer Targeted Nanoparticles Specifically Induce Apoptosis in Cancer Cells and Spare Normal Cells

2012 ◽  
Vol 65 (1) ◽  
pp. 5 ◽  
Author(s):  
Jagat R. Kanwar ◽  
Rupinder K. Kanwar ◽  
Ganesh Mahidhara ◽  
Chun Hei Antonio Cheung
Keyword(s):  
Adverse Effects ◽  
Cancer Cells ◽  
Modern Medicine ◽  
Chemotherapeutic Agents ◽  
Locked Nucleic Acid ◽  
Cancer Drug ◽  
Drug Induced ◽  
Normal Cells

Curing cancer is the greatest challenge for modern medicine and finding ways to minimize the adverse effects caused by chemotherapeutic agents is of importance in improving patient’s physical conditions. Traditionally, chemotherapy can induce various adverse effects, and these effects are mostly caused by the non-target specific properties of the chemotherapeutic compounds. Recently, the use of nanoparticles has been found to be capable of minimizing these drug-induced adverse effects in animals and in patients during cancer treatment. The use of nanoparticles allows various chemotherapeutic drugs to be targeted to cancer cells with lower dosages. In addition to this, the use of nanoparticles also allows various drugs to be administered to the subjects by an oral route. Here, locked nucleic acid (LNA)-modified epithelial cell adhesion molecules (EpCAM), aptamers (RNA nucleotide), and nucleolin (DNA nucleotide) aptamers have been developed and conjugated on anti-cancer drug-loaded nanocarriers for specific delivery to cancer cells and spare normal cells. Significant amounts of the drug loaded nanocarriers (92 ± 6 %) were found to distribute to the cancer cells at the tumour site and more interestingly, normal cells were unaffected in vitro and in vivo. In this review, the benefits of using nanoparticle-coated drugs in various cancer treatments are discussed. Various nanoparticles that have been tried in improving the target specificity and potency of chemotherapeutic compounds are also described.

scholarly journals Anticancer Effect of Fucoidan in Combination with Tyrosine Kinase Inhibitor Lapatinib

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Byeongsang Oh ◽  
Jihun Kim ◽  
Weidong Lu ◽  
David Rosenthal
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Kinase Inhibitor ◽  
Cell Types ◽  
Anticancer Effect ◽  
Inhibit Cell Growth ◽  
Mechanism Of Interaction ◽  
Synergistic Antitumor Activity

Background. Despite a number ofin vitroandin vivostudies reporting the efficacy of fucoidan in treating various cancers, few studies have measured the efficacy of dietary fucoidan (DF) in combination with cancer drugs. Thus, we examined the sensitivity of DF in combination with the EGFR/ERBB2-targeting reagent lapatinib on cancer cells.Method. We selected six EGFR/ERBB2-amplified cancer cell lines (OE19, NCI-N87, OE33, ESO26, MKN7, and BT474) as anin vitromodel and tested their sensitivity to DF alone and to DF in combination with the well-known EGFR/ERBB2-targeting reagent lapatinib.Result. Overall, in drug independent sensitivity test, DF alone did not significantly inhibit the growth of EGFR/ERBB2-amplified cancer cellsin vitro. When DF was given in combination with lapatinib, however, it tended to synergistically inhibit cell growth in OE33 but antagonized the action of lapatinib in ESO26, NCI-N87, and OE19.Conclusion. This study suggests that DF has the potential to increase or decrease the effects of certain anticancer drugs on certain cancer cell types. Further study is needed to explore the mechanism of interaction and synergistic antitumor activity of DF in combination with chemotherapy and targeted therapy.

scholarly journals Involvement of Histone Lysine Methylation in p21 Gene Expression in Rat KidneyIn Vivoand Rat Mesangial CellsIn Vitrounder Diabetic Conditions

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Xiangjun Li ◽  
Chaoyuan Li ◽  
Xiaoxia Li ◽  
Peihe Cui ◽  
Qifeng Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Mesangial Cells ◽  
Histone H3 ◽  
Diabetic Rats ◽  
Lysine Methylation ◽  
Histone Lysine Methylation ◽  
Histone Lysine

Diabetic nephropathy (DN), a common complication associated with type 1 and type 2 diabetes mellitus (DM), characterized by glomerular mesangial expansion, inflammation, accumulation of extracellular matrix (ECM) protein, and hypertrophy, is the major cause of end-stage renal disease (ESRD). Increasing evidence suggested that p21-dependent glomerular and mesangial cell (MC) hypertrophy play key roles in the pathogenesis of DN. Recently, posttranscriptional modifications (PTMs) have uncovered novel molecular mechanisms involved in DN. However, precise regulatory mechanism of histone lysine methylation (HKme) mediating p21 related hypertrophy associated with DN is not clear. We evaluated the roles of HKme and histone methyltransferase (HMT) SET7/9 in p21 gene expression in glomeruli of diabetic rats and in high glucose- (HG-) treated rat mesangial cells (RMCs). p21 gene expression was upregulated in diabetic rats glomeruli; chromatin immunoprecipitation (ChIP) assays showed decreased histone H3-lysine9-dimethylation (H3K9me2) accompanied with enhanced histone H3-lysine4-methylation (H3K4me1/3) and SET7/9 occupancies at the p21 promoter. HG-treated RMCs exhibited increased p21 mRNA, H3K4me level, SET7/9 recruitment, and inverse H3K9me, which were reversed by TGF-β1 antibody. These data uncovered key roles of H3Kme and SET7/9 responsible for p21 gene expressionin vivoandin vitrounder diabetic conditions and confirmed preventive effect of TGF-β1 antibody on DN.

scholarly journals Investigation of Nano-Bio Interactions within a Pancreatic Tumor Microenvironment for the Advancement of Nanomedicine in Cancer Treatment

2021 ◽  
Vol 28 (3) ◽  
pp. 1962-1979
Author(s):  
Abdulaziz Alhussan ◽  
Kyle Bromma ◽  
Ece Pinar Demirci Bozdoğan ◽  
Andrew Metcalfe ◽  
Joanna Karasinska ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Pancreatic Tumor ◽  
Cell Types ◽  
Time Period ◽  
Physical And Chemical ◽  
Pancreatic Origin

Pancreatic cancer is one of the deadliest types of cancer, with a five-year survival rate of only 10%. Nanotechnology offers a novel perspective to treat such deadly cancers through their incorporation into radiotherapy and chemotherapy. However, the interaction of nanoparticles (NPs) with cancer cells and with other major cell types within the pancreatic tumor microenvironment (TME) is yet to be understood. Therefore, our goal is to shed light on the dynamics of NPs within a TME of pancreatic origin. In addition to cancer cells, normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) were examined in this study due to their important yet opposite roles of suppressing tumor growth and promoting tumor growth, respectively. Gold nanoparticles were used as the model NP system due to their biocompatibility and physical and chemical proprieties, and their dynamics were studied both quantitatively and qualitatively in vitro and in vivo. The in vitro studies revealed that both cancer cells and CAFs take up 50% more NPs compared to NFs. Most importantly, they all managed to retain 70–80% of NPs over a 24-h time period. Uptake and retention of NPs within an in vivo environment was also consistent with in vitro results. This study shows the paradigm-changing potential of NPs to combat the disease.

scholarly journals Different Inhibitory Effect and Mechanism of Hydroxyapatite Nanoparticles on Normal Cells and Cancer Cells In Vitro and In Vivo

2014 ◽  
Vol 4 (1) ◽  
Author(s):  
Yingchao Han ◽  
Shipu Li ◽  
Xianying Cao ◽  
Lin Yuan ◽  
Youfa Wang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Inhibitory Effect ◽  
Hydroxyapatite Nanoparticles ◽  
Normal Cells

scholarly journals Methyl Jasmonate: Putative Mechanisms of Action on Cancer Cells Cycle, Metabolism, and Apoptosis

2014 ◽  
Vol 2014 ◽  
pp. 1-25 ◽  
Author(s):  
Italo Mario Cesari ◽  
Erika Carvalho ◽  
Mariana Figueiredo Rodrigues ◽  
Bruna dos Santos Mendonça ◽  
Nivea Dias Amôedo ◽  
...  
Keyword(s):  
Methyl Jasmonate ◽  
Cancer Cells ◽  
Anion Channel ◽  
Atp Depletion ◽  
Voltage Dependent Anion Channel ◽  
Normal Cells ◽  
Antiapoptotic Proteins ◽  
Mitochondrial Functions

Methyl jasmonate (MJ), an oxylipid that induces defense-related mechanisms in plants, has been shown to be active against cancer cells bothin vitroandin vivo, without affecting normal cells. Here we review most of the described MJ activities in an attempt to get an integrated view and better understanding of its multifaceted modes of action. MJ (1) arrests cell cycle, inhibiting cell growth and proliferation, (2) causes cell death through the intrinsic/extrinsic proapoptotic, p53-independent apoptotic, and nonapoptotic (necrosis) pathways, (3) detaches hexokinase from the voltage-dependent anion channel, dissociating glycolytic and mitochondrial functions, decreasing the mitochondrial membrane potential, favoring cytochromecrelease and ATP depletion, activating pro-apoptotic, and inactivating antiapoptotic proteins, (4) induces reactive oxygen species mediated responses, (5) stimulates MAPK-stress signaling and redifferentiation in leukemia cells, (6) inhibits overexpressed proinflammatory enzymes in cancer cells such as aldo-keto reductase 1 and 5-lipoxygenase, and (7) inhibits cell migration and shows antiangiogenic and antimetastatic activities. Finally, MJ may act as a chemosensitizer to some chemotherapics helping to overcome drug resistant. The complete lack of toxicity to normal cells and the rapidity by which MJ causes damage to cancer cells turn MJ into a promising anticancer agent that can be used alone or in combination with other agents.

scholarly journals LIMK1 promotes peritoneal metastasis of gastric cancer and is a therapeutic target

Oncogene ◽  
2021 ◽  
Author(s):  
Xi Kang ◽  
Weilin Li ◽  
Weixin Liu ◽  
Han Liang ◽  
Jingyu Deng ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Peritoneal Metastasis ◽  
Therapeutic Target ◽  
Migration And Invasion ◽  
Gastric Cancer Cells ◽  
Cell Migration And Invasion

AbstractPeritoneal metastasis is a common form of metastasis among advanced gastric cancer patients. In this study, we reported the identification of LIM domain kinase 1 (LIMK1) as a promoter of gastric cancer peritoneal metastasis, and its potential to be a therapeutic target of dabrafenib (DAB). Using transcriptomic sequencing of paired gastric cancer peritoneal metastasis, primary tumors, and normal gastric tissues, we first unveiled that LIMK1 is selectively up-regulated in metastatic tumors. Increased LIMK1 in gastric cancer peritoneal metastasis was validated by immunohistochemistry analysis of an independent patient cohort. In vitro functional studies demonstrated that LIMK1 knockout or knockdown significantly inhibited cell migration and invasion of gastric cancer cells. LIMK1 knockout also abrogated peritoneal and liver metastases of gastric cancer cells in nude mice in vivo. Dabrafenib, a small molecule targeting LIMK1, was found to decrease cell migration and invasion of gastric cancer cells in vitro and abolish peritoneal and liver metastasis formation in vivo. Mechanistically, either LIMK1 knockout or Dabrafenib inhibited LIMK1 expression and phosphorylation of its downstream target cofilin. Taken together, our results demonstrated that LIMK1 functions as a metastasis promoter in gastric cancer by inhibiting LIMK1-p-cofilin and that Dabrafenib has the potential to serve as a novel treatment for gastric cancer peritoneal metastasis.

scholarly journals Palladium nanoparticles encapsulated with resveratrol-derived phenols and polyphenols for targeted prostate cancer therapy

2019 ◽  
Author(s):  
◽  
Velaphi Clement Thipe
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Palladium Nanoparticles ◽  
Gum Arabic ◽  
Prostate Tumor ◽  
Laminin Receptor ◽  
Prostate Cancer Cells ◽  
Normal Cells

The main goal of this dissertation was to explore the development of a new generation of green nanoformulations through the production of biocompatible palladium nanoparticles using resveratrol to treat, image and evaluate the efficacy of the formulations in prostate cancer cells with minimal toxicity to surrounding normal tissues. This dissertation is classified into three parts with three main objectives of the producing and characterizing resveratrol-derived phenols and polyphenols encapsulated palladium nanoparticles (Res-PdNPs) for the imaging and treatment of prostate cancer. Rigorous studies were performed for the optimization of the synthesis to achieve increased resveratrol-derived phenols and polyphenols corona loading on the palladium nanoparticle surface capable of providing adjuvant therapeutic benefits through delivering potent doses of both resveratrol phenols and nanoparticles directly to prostate cancer cells. A total of four formulations were produced Res-PdNP-1 (resveratrol-palladium nanoparticles), Res-PdNP-2 (increased resveratrol corona loaded palladium nanoparticles), Res-PdNP-3 (resveratrol-gum arabic stabilized palladium nanoparticles) and Res-PdNP-4 (increased resveratrol corona loaded and compacted with gum arabic stabilized palladium nanoparticles), respectively. Electron microscopic (TEM) results revealed that role of gum arabic was not limited to the stability of the nanoparticles but also facilitated the crystallization of the produced palladium nanoparticles (Res-PdNP-3 and Res-PdNP-4) and subsequently provided a supportive matrix for increased resveratrol phenols loading capacity. In vitro evaluation of the Res-PdNPs showed that Res-PdNP-1 and Res-PdNP-2, were not stable in serum while Res-PdNP-3 and Res-PdNP-4 maintained superior stability, thus ruling out further analysis using Res-PdNP-1 and Res-PdNP-2. The LC-MS/MRM results confirmed increased resveratrol phenols loading in Res-PdNP-4 when compared to Res-PdNP-3; consequently Res-PdNP-4 nanoparticles were confirmed as the ideal nanoformulation to improve the bioavailability, biodistribution and emblematize as an adjuvant therapy to induce selective and specific tumor-cell-death. The prostate tumor selective and specific affinity of Res-PdNP-4 nanoparticles through numerous cellular internalization studies undoubtedly revealed that Res-PdNP-4 nanoparticles can be internalized into prostate cancer cells via laminin receptor-mediated endocytosis which are receptors overexpressed on prostate cancer cells compared to normal cells. The Res-PdNP-4 nanoparticles were evaluated to investigate in vitro cellular toxicity against both prostate cancer (PC-3) cells and normal human aortic endothelial cells (HAEC). Results indicated that Res-PdNP-4 exhibited comparable anticancer efficacy against prostate cancer cells as chemotherapeutic drugs (cisplatin and etoposide). However, the results showed that cisplatin and etoposide treatments were highly toxic to normal cells while Res-PdNP-4 nanoparticles presented no toxicity further corroborating laminin receptor-mediated delivery, making Res-PdNP-4 nanoparticles selective and specific to prostate cancer cells. Res-PdNP-4 nanoparticles were investigated in vivo using a human prostate tumor-bearing severely combined immunodeficient (SCID) male mice as the animal model to evaluate Res-PdNP-4 nanoparticles ability to control or reduce prostate tumor size. The in vivo results of Res-PdNP-4 showed a good dose response which was well tolerated by the animals, as no animal health problems and discomfort was observed as evidenced by body weight/eating habits of animals. Although further studies are required to determine a better dose to see increased efficacy. This study was performed through intravenous (IV) administration of the Res-PdNP-4, intraperitoneal (IP) delivery and direct injection into the tumor may show a better response as has been the case with many different types of nanoparticles. In conclusion, the therapeutic efficacy results showed that Res-PdNP-4 have significant therapeutic effect and are able to control the tumor size in comparison to the saline control and free resveratrol treated groups. This was due to the high corona of resveratrol-derived phenols and polyphenols on the PdNPs facilitating effectively enhanced delivery of resveratrol with high bioavailability, giving an advantage in tumor therapy.

Sign in / Sign up

Export Citation Format

Share Document