Anticarcinoma Activity Research Articles

Cell membrane-camouflaged bufalin targets NOD2 and overcomes multidrug resistance in pancreatic cancer.

Multidrug resistance in pancreatic cancer poses a significant challenge in clinical treatment. Bufalin (BA), a compound found in secretions from the glands of toads, may help overcome this problem. However, severe cardiotoxicity thus far has hindered its clinical application. Hence, the present study aimed to develop a cell membrane-camouflaged and BA-loaded polylactic-co-glycolic acid nanoparticle (CBAP) and assess its potential to counter chemoresistance in pancreatic cancer. The toxicity of CBAP was evaluated by electrocardiogram, body weight, distress score, and nesting behavior of mice. In addition, the anticarcinoma activity and underlying mechanism were investigated both in vitro and in vivo. CBAP significantly mitigated BA-mediated acute cardiotoxicity and enhanced the sensitivity of pancreatic cancer to several clinical drugs, such as gemcitabine, 5-fluorouracil, and FOLFIRINOX. Mechanistically, CBAP directly bound to nucleotide-binding and oligomerization domain containing protein 2 (NOD2) and inhibited the expression of nuclear factor kappa-light-chain-enhancer of activated B cells. This inhibits the expression of ATP-binding cassette transporters, which are responsible for chemoresistance in cancer cells. Our findings indicate that CBAP directly inhibits NOD2. Combining CBAP with standard-of-care chemotherapeutics represents a safe and efficient strategy for the treatment of pancreatic cancer.

Matairesinol Induces Mitochondrial Dysfunction and Exerts Synergistic Anticancer Effects with 5-Fluorouracil in Pancreatic Cancer Cells.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of cancer and exhibits a devastating 5-year survival rate. The most recent procedure for the treatment of PDAC is a combination of several conventional chemotherapeutic agents, termed FOLFIRINOX, that includes irinotecan, leucovorin, oxaliplatin, and 5-fluorouracil (5-FU). However, ongoing treatment using these agents is challenging due to their severe side effects and limitations on the range of patients available for PDAC. Therefore, safer and more innovative anticancer agents must be developed. The anticarcinoma activity of matairesinol that can be extracted from seagrass has been reported in various types of cancer, including prostate, breast, cervical, and pancreatic cancer. However, the molecular mechanism of effective anticancer activity of matairesinol against pancreatic cancer remains unclear. In the present study, we confirmed the inhibition of cell proliferation and progression induced by matairesinol in representative human pancreatic cancer cell lines (MIA PaCa-2 and PANC-1). Additionally, matairesinol triggers apoptosis and causes mitochondrial impairment as evidenced by the depolarization of the mitochondrial membrane, disruption of calcium, and suppression of cell migration and related intracellular signaling pathways. Finally, matairesinol exerts a synergistic effect with 5-FU, a standard anticancer agent for PDAC. These results demonstrate the therapeutic potential of matairesinol in the treatment of PDAC.

Novel chlorpromazine derivatives as anti-endometrial carcinoma agents with reduced extrapyramidal side effects

As the traditional conservative remedy for endometrial carcinoma (EC), progesterone has great limitations due to its poor performance, and a new strategy is urgently needed. Our previous work revealed that the antipsychotic drug chlorpromazine (CPZ) has stronger antitumor activity on EC than progesterone does, which may provide a promising conservative alternative for EC patients. Unfortunately, the severe extrapyramidal symptoms (EPSs) at concentrations (>5 mg/kg) that are required for anticarcinoma activity limited its repurposing. Therefore, a series of novel CPZ derivatives were designed and synthesized to avoid EPS and retain its antitumor activity. Among them, 11·2HCl and 18 displayed greater inhibitory activity by modulating SOS1. Notably, even at a dose of 100 mg/kg, 11·2HCl/18 had little effect on the extrapyramidal system. In conclusion, 11·2HCl and 18 greatly repressed the malignant features of endometrial carcinoma and decreased extrapyramidal side effects compared with the original drug CPZ.

One‐pot microwave‐assisted synthesis of dialkytin 2‐[(4‐methylbenzoyl) hydrazono]‐3‐phenylpropanoic acid complexes and their anticarcinoma activities and DNA‐binding properties

AbstractUnder microwave irradiation, five organotin complexes were produced through the reaction of 4‐methylbenzhydrazide, sodium phenylpyruvate and corresponding dialkyltin. Fourier transform infrared spectroscopy; 1H, 13C and 119Sn nuclear magnetic resonance spectroscopy; high‐resolution mass spectrometry; X‐ray crystallography and thermogravimetric analysis (TGA) were performed to characterise the synthesised complexes. The in vitro antitumour activity for the complexes involved was assessed using the MTT assay on the human carcinoma cells of HepG2, NCI‐H460 and MCF7. 2‐Oxo‐3‐pheny propionic acid p‐methyl benzoylhydrazone dibutyltin, C5, exhibited an intensive anticarcinoma activity. Cell apoptosis revealed that C5 mediated the cell apoptosis of HepG2 cells. DNA binding in C5 was investigated through UV‐visible absorption spectrometry and viscosity measurement. Molecular docking was performed for predicting C5‐DNA binding, which revealed C5 could be implanted into the DNA double helix.

Pharmaceutical immunoglobulin G impairs anti-carcinoma activity of oxaliplatin in colon cancer cells

BackgroundRecent evidence proves that intravenous human immunoglobulin G (IgG) can impair cancer cell viability. However, no study evaluated whether IgG application benefits cancer patients receiving chemotherapeutics.MethodsInfluence of pharmaceutical-grade human IgG on the viability of a series of patient-derived colon cancer cell lines with and without chemotherapeutic intervention was determined. Cell death was analysed flow cytometrically. In addition, the influence of oxaliplatin and IgG on the ERK1/2-signalling pathway was evaluated by western blots.ResultsWe evaluated the effects of pharmaceutical IgG, such as PRIVIGEN® IgG and Tonglu® IgG, in combination with chemotherapeutics. We did not observe any significant effects of IgG on tumour cell viability directly; however, human IgG significantly impaired the anti-tumoral effects of oxaliplatin. Primary cancer cell lines express IgG receptors and accumulate human IgG intracellularly. Moreover, while oxaliplatin induced the activation of ERK1/2, the pharmaceutical IgG inhibited ERK1/2 activity.ConclusionsThe present study demonstrates that pharmaceutical IgG, such as PRIVIGEN® IgG and Tonglu® IgG, can impair the anti-carcinoma activity of oxaliplatin. These data strongly suggest that therapeutic IgG as co-medication might have harmful side effects in cancer patients. The clinical significance of these preclinical observations absolutely advises further preclinical, as well as epidemiological and clinical research.

SRT2183 impairs ovarian cancer by facilitating autophagy.

The 5-year survival rate of ovarian cancer patients is only 47%, and developing novel drugs for ovarian cancer is needed. Herein, we evaluated if and how SRT2183, a sirtuin-1 activator, impairs the ovarian cancer cells. OVCAR-3 and A2780 cells were treated with SRT2183. Cell viability was measured by cell counting kit-8 assay and clonogenic assay. Apoptosis was determined by flow cytometry with Annexin V and propidium iodide. The level of autophagy was evaluated by western blot and immunofluorescence. The activities of AKT/mTOR/70s6k and MAPK signaling pathway were measured by immunoblot. SRT2183 inhibited the growth of ovarian cancer cells, increased the accumulation of BAX, cleaved-caspase 3 and cleaved-PARP, and decreased the level of anti-apoptotic Bcl-2 and Mcl-1. SRT2183 increased the LC3II level, and enhanced the degradation of p62/SQSTM1. SRT2183 increased the formation of GFP-LC3 puncta and induced the maturation of autophagosome. Interestingly, knockdown of autophagy related 5 and 7 significantly impaired the anti-carcinoma activity of SRT2183, implying that SRT2183 impaired the ovarian cancer cells by inducing autophagy. SRT2183 decreased the accumulation of p-Akt, p-mTOR and p-70s6k, and activated the p38 MAPK signaling pathway. This indicated that Akt/mTOR/70s6k and p38 MAPK signaling pathway might be involved in the SRT2183-mediated autophagy and apoptosis.

Cucurbitacin E inhibits esophageal carcinoma cell proliferation, migration, and invasion by suppressing Rac1 expression through PI3K/AKT/mTOR pathway.

As an oxygenated tetracyclic triterpenoid, Cucurbitacin E (CuE) possesses potential antitumor properties in sorts of malignancies. However, its effect on human esophageal carcinoma cells has not been previously unearthed, and the mechanism underlying its anticarcinoma activity remains vague. Hence, this study was arranged to probe the function of CuE on esophageal carcinoma cells and its specific mechanism. Human esophageal carcinoma cells (ECA109 and EC9706) and human normal esophageal epithelial cells (Het-1A) were selected for subsequent experiments. The expression levels of Rac1 in esophageal carcinoma cells were measured. After transfection of sh-Rac1 or pCDNA3.1-Rac1, esophageal carcinoma cells were exposed to CuE. Then, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and 5-ethynyl-2'-deoxyuridine staining were utilized for measurement of cell proliferation ability, cell scratch assay for inspection of cell migration rate, and Transwell for detection of cell invasion ability. The phosphorylation levels of protein kinase B and mTOR were analyzed by Western blot. Rac1 was highly expressed in esophageal carcinoma cells. Transfection of sh-Rac1 in esophageal carcinoma cells resulted in suppression on cell proliferation, migration, and invasion, as well as downregulated phosphorylation levels of AKT and mammalian target of rapamycin (mTOR) in esophageal carcinoma cells, while transfection of pCDNA3.1-Rac1 had an opposite effect, implicating that Rac1 can promote the viability of esophageal carcinoma cells. Esophageal carcinoma cells subjected to CuE treatment had decreased expression of Rac1, suppressed cell viability, and decreased phosphorylation levels of AKT and mTOR. Transfection of pCDNA3.1-Rac1 and CuE treatment in esophageal carcinoma cells enhanced viability of esophageal carcinoma cells and promoted the phosphorylation levels of AKT and mTOR in comparison with cells treated with CuE alone. CuE inhibits proliferation, invasion, and migration of esophageal carcinoma cells via downregulating Rac1 to block the phosphoinositide 3-kinase/AKT/mTOR pathway.

Cardiac Glycoside Compound Isolated from Helleborus thibetanus Franch Displays Potent Toxicity against HeLa Cervical Carcinoma Cells through ROS-Independent Autophagy.

The current study aimed to examine the anticancer activity of HTF-1, a cardiac glycoside (CG) isolated from Helleborus thibetanus Franch, using a cell-based model and to discover the underlying mechanisms with specific focus on autophagy. We found that HTF-1 was able to potently decrease the viability of several cancer cell lines especially for HeLa cervical carcinoma cells. It was discovered that HTF-1 dose dependently induced overproduction of ROS in HeLa cells, and the cell viability can be rescued when adding ROS scavenger N-acetyl-l-cysteine (NAC). More, we found that HTF-1 induced ROS-independent autophagy in concentration- and time-dependent manners in HeLa cells. This can be collectively verified by LC3-II and p62 abundance and also eGFP-LC3 puncta assay, bafilomycin clamp experiment, and acidotropic dye fluorescent labeling experiment. Additionally, TEM examination showed more autophagic vacuoles for HTF-1-treated HeLa cells. In HeLa cells, pretreatment with wortmannin (an inhibitor of the initial stages of autophagy to block autophagosome formation, thus, it should weaken the autophagy induction effect of HTF-1) decreased the autophagic flux and partially antagonized cell death induced by HTF-1, indicating that autophagy induced by HTF-1 played a cancer-suppressing role. Furthermore, coadministration of BAF (as a distal inhibitor of autophagy) with HTF-1 demonstrated a synergistic anticancer effect against HeLa cells. We believe that our work will enrich the understanding of CGs and especially anticarcinoma activity, also, pave the way for natural-product-based anticancer drug development.

Characterization, antioxidativity, and anti-carcinoma activity of exopolysaccharide extract from Rhodotorula mucilaginosa CICC 33013

The water-soluble exopolysaccharide REPS2-A was isolated and characterized from R. mucilaginosa CICC 33013. REPS2-A was composed of galactose, arabinose, glucose, and mannose at a molar ratio of 63.1:0.2:18.3:18.3, respectively, with a molecular weight of 7.125×106Da. Based on FT-IR, NMR, and methylation analysis, REPS2-A was identified to be a highly branched polysaccharide with a backbone of (1→3)-linkedGal with Man, Gal, and Ara terminals. The branches were identified as (1→2)-linked Glc, (1→4)-linked Man, (1→3)-linked Glc, (1→4,6)-linked Man, and (1→2,3,4)-linked Ara. In addition, REPS2-A exhibited excellent free radical scavenging (DPPH, ABTS, and reducing power) and antitumor activities. These results indicate its activity against growth of the human hepatocarcinoma cell HepG2 with IC50 values of 1.0mg/mL, compared to lower cytotoxic effects on normal human hepatocyte cell L02. Studying the underlying mechanisms indicated that REPS2-A induced both dose- and time-dependent cell cycle arrest at the G1/S phase.

Lobaplatin Inhibits the Proliferation of Hepatollular Carcinoma Through P53 Apoptosis Axis

Cancer is a major killer nowadays, just as its name-a kind of hideous arthropods- which always goes through everywhere without restraints. little is known about how to repress its proliferation and destroy its defense. A lot of researchers focus on the antineoplastic agents which may suppress the proliferation and metastasis of Hepatocellular carcinoma(HCC) (1). HCC is the sixth most common tumor and the third leading cause of cancer deaths worldwide, particularly in Eastern Asia (2). Every year, billions of money is put into the researches about new drug account for HCC and the mechanism on apoptosis and cell cycle arrest of hepatoma cells (1, 3) Then the third generation platinum compounds emerge in time for the demand. Lobaplatin (D-19466;1,2- diammino-methyl-cyclobutaneplatium (II)-lactate) is one of platinum compounds and has presented encouraged anti-carcinoma activity in HCC without significant hepatotoxicity (4).

Anti-carcinoma Activity of Polyphenolic Extract of Ichnocarpus frutescens

Dietary polyphenol antioxidants are known to decrease the risk of many diseases such as cancer and cardiovascular diseases [1]. In this study polyphenolic extract (PPE) of leaves of Ichnocarpus frutescens was evaluated for antitumor activity in vivo. Murine Ehrlich ascites carcinoma (EAC) model was used to assess PPE antitumor activity in vivo [2]. PPE cytotoxicity was determined in vitro in U-937 monocytoid leukemia and K-562 erythroleukemia cell lines. The total phenolics content was quantified by the Folin-Ciocalteu method [3]. Results of in vivo study showed a significant decrease in tumor volume, viable tumor cell count and a significant increase of life span in the PPE treated group compared to untreated one: the life span of PPE treated animals increased by 53.41% (50 mg PPE/kg) and 73.95% (100 mg PPE/kg). PPE (5, 10 and 20 µg/mL) effectively inhibits in vitro proliferation of U-937 and K-562 cell lines. The in vitro and in vivo anti-tumor activity of PPE from Ichnocarpus frutescens could be due to rich polyphenols and flavonoids [4]. Acknowledgements: All India Council of Technical Education (AICTE), Government of India, New Delhi, India is greatly acknowledged.

Potent Anticarcinoma Activity of the Humanized Anti-CD70 Antibody h1F6 Conjugated to the Tubulin Inhibitor Auristatin via an Uncleavable Linker

The antitubulin agent monomethyl auristatin F (MMAF) induces potent antitumor effects when conjugated via protease cleavable linkers to antibodies targeting internalizing, tumor-specific cell surface antigens. Humanized 1F6 (h1F6) is a humanized monoclonal antibody targeting CD70, a member of the tumor necrosis factor family that is expressed on hematologic malignancies and carcinomas. Here, we tested h1F6-maleimidocaproyl (mc) MMAF conjugates, consisting of an uncleavable mc linker, for their ability to interfere with the growth of CD70-positive carcinomas. To evaluate the optimal drug per antibody ratio, we conjugated either four or eight MMAF molecules to the cysteines that comprise the interchain disulfides of h1F6 and determined antitumor activities in vitro and in xenografted mice. The tumor types tested included glioblastoma, patient-derived renal cell carcinoma (RCC) cell isolates, and standard RCC tumor cell lines. All h1F6-mcMMAF conjugates potently interfered with the growth of all carcinomas in vitro and resulted in complete responses of RCC tumors implanted orthotopically or s.c. in mice. In vitro, h1F6-mcMMAF(8) was generally more potent than h1F6-mcMMAF(4). However, h1F6-mcMMAF(4) displayed equal or better efficacy than h1F6-mcMMAF(8) when administered to tumor-bearing mice. We showed that h1F6-mcMMAF conjugates inhibited the growth of human carcinomas and that increased drug loading, while improving potency in vitro, did not substantially affect the pharmacodynamic and pharmacokinetic properties in vivo. Based on these findings, h1F6-mcMMAF(4), designated SGN-75, has been identified as a potential antibody-drug conjugate for clinical development.

Increasing Anticarcinoma Activity of an Anti-erbB2 Recombinant Immunotoxin by the Addition of an Anti-EpCAM sFv

erbB2, the product of the Her2-neu gene, is a well-established therapeutic target for antibody-based biologicals, but anti-erbB2 antibody-toxin fusion proteins are limited in their activity. The goal of this study was to determine if genetically adding an sFv targeting epithelial cell adhesion molecule (EpCAM) to an anti-Her2 sFv immunotoxin would result in enhanced antitumor activity. In vitro studies were done in which the new bispecific immunotoxin DTEpCAM23 was compared with monospecific immunotoxins (DTEpCAM and DT23) to quantitate immunotoxin activity. Mixtures of monospecific immunotoxins were tested to determine if they were as effective as the bispecific immunotoxin. Binding and internalization studies were also done. In vivo, bispecific immunotoxins were given i.t. to athymic nude mice bearing HT-29 human colon cancer flank tumors and i.p. to mice with i.p. tumors. DTEpCAM23 bispecific immunotoxins showed far greater activity than monospecific immunotoxin (sometimes over 2,000-fold) against most tumor lines. Bispecific immunotoxin was superior and selective in its activity against different carcinoma cell lines. Bispecific immunotoxin had greater activity than monospecific immunotoxin indicating an advantage of having both sFv on the same single-chain molecule. Binding and internalization studies did not explain the differences between bispecific immunotoxin and monospecific immunotoxin activity. Orientation of the sFvs on the molecule had a significant effect on in vitro and in vivo properties. The bispecific immunotoxins were more effective than the monospecific immunotoxin in the flank tumor mouse model. The synthesis of bispecific immunotoxin created a new biological agent with superior in vitro and in vivo activity (over monospecific immunotoxin), more broad reactivity, more efficacy against tumors in vivo, and diminished toxic effects in mice.

Micellar Delivery System for Dequalinium—A Lipophilic Cationic Drug with Anticarcinoma Activity

Delocalized lipophilic cations (DLC) such as dequalinium (DQA) comprise a novel class of antitumor agents. They are more selectively toxic to carcinoma cells in comparison to non-transformed epithelial cells. In addition, DLC’s have also been shown to enhance the efficacy of existing anticancer modalities such as radiation and photodynamic therapies. A severe drawback of these attractive novel anticancer agents is their limited solubility in aqueous solutions. To overcome this obstacle, we tried to incorporate DQA into liposomes and micelles. We found that incorporation in liposomes does not seem to be possible at physiological salt concentrations. However, we succeeded in preparing micelles made of polyethylene glycol derivatives of phosphatidy-lethanolamine (PEG-PE) which stably bind up to 30 mol % DQA.

ヌードマウス可移植性ヒト下顎骨由来骨肉腫累代株の樹立およびＲｈｏｄａｍｉｎｅ‐１２３の制癌効果

Osteosarcoma is high malignant neoplasm and the prognosis is poor. We established transplantable strains of nude mouse derived from human osteosarcoma originating in mandible (HOSMN-1) and experimented on anticarcinoma activity of Rhodamine-123, a mitochondrial specific dye, and the following results were obtained.(1) Histologically, HOSMN-1 consisted of atypical spindle, polygonal cells and bizarre multinucleated giant cells, and collagen fibers were also identified. In some places, storiform like pattern was revealed.(2) Both alkaline phosphatase (ALP) and acid phosphatase (ACP) stains showed positive granules in the tumor cells.(3) In chromosomal analysis, it was confirmed that HOSMN-1 was of the human origin. We have maintained the tumor cells for about 2 years for 10 serial passages, but up to date, no malignant osteoid was identified. HOSMN-1 hadn't revealed any differentiation or dis-differentiation.(4) On anticarcinoma activity of Rhodamine-123, a group administered 15 mg/kg × 4 times (i.m.) had significantly showed a growth inhibition effect in comparison with a control group, and the disappearance of tumor in 30% was observed.(5) Ultrastructurelly, in a group administered Rhodamine-123, especially, mitochondrial expansion, distortion and disappearance of crista were markedly seen. These findings supported the contention that Rhodamine-123 is a specific mitochondrial dye.

Functional impairment induced by lipophilic cationic compounds on mitochondria.

Lipophilic cations, such as rhodamine 123, have selective anticarcinoma activity both in epithelial-derived tumor cells and in tumor cells injected into mice. The mechanism by which rhodamine 123 and safranin have their effect on mitochondrial function was examined. Rhodamine 123 and safranin inhibit the stimulation of mitochondrial respiration by ADP in a similar concentration range. This inhibition occurs whether the mitochondria are respiring on succinate as a substrate or on ascorbate plus tetramethylphenylenediamine. ATP hydrolysis was stimulated twofold by high lipophilic cation concentration. These results demonstrate that rhodamine 123 and safranin affect oxidative phosphorylation in a similar fashion.

Dequalinium, a topical antimicrobial agent, displays anticarcinoma activity based on selective mitochondrial accumulation.

Positively charged lipophilic compounds, such as rhodamine 123, localize in mitochondria and are selectively accumulated and retained by carcinoma cells. It has been suggested that this phenotype may be exploited for selective killing of carcinoma cells by lipophilic cations. Here we report that doubly positively charged dequalinium, which has been used for 30 years as an antimicrobial agent in over-the-counter mouthwashes, lozenges, ointments, and paints, exhibits significant anticarcinoma activity. Dequalinium is more effective than seven of eight established anticancer drugs in prolonging the survival of mice with intraperitoneally implanted mouse bladder carcinoma MB49. Dequalinium also inhibits the growth of subcutaneously implanted human colon carcinoma CX-1 in nude mice and recurrent rat colon carcinoma W163 in rats. Lipophilic cationic compounds, such as dequalinium, could comprise a unique class of anticarcinoma agents.

Possible biochemical basis for the anticarcinoma activity of rhodamines

Possible biochemical basis for the anticarcinoma activity of rhodamines

Rhodamine 123 inhibits bioenergetic function in isolated rat liver mitochondria

Rhodamine 123 accumulates in the mitochondria of living cells and exhibits selective anticarcinoma activity. The biochemical basis of toxicity was investigated by testing the effect of the dye on isolated rat liver mitochondria. Much lower concentrations of rhodamine 123 were required to inhibit ADP-stimulated respiration and ATP synthesis in well-coupled energized mitochondria than were required to inhibit uncoupled respiration and uncoupler-stimulated ATP hydrolysis. The amount of rhodamine 123 associated with the mitochondria was several-fold greater under energized as compared to non-energized conditions, which may explain why coupled functions appeared to be more sensitive than uncopuled functions to inhibition at low concentrations of rhodamine 123. It was concluded that the site of rhodamine 123 inhibition is most likely the F 0F 1ATPase complex and possibly electron transfer reactions as well.

Anticarcinoma activity in vivo of rhodamine 123, a mitochondrial-specific dye.

Carcinoma cells and normal epithelial cells differ in the mitochondrial retention of a permeant cationic compound, rhodamine 123. The possibility of utilizing this difference in carcinoma chemotherapy was investigated. Rhodamine 123 exhibited anticarcinoma activity in mice, and this activity was potentiated by 2-deoxyglucose.