Moderate Growth Inhibitory Effects Research Articles

Nitrogen-doped carbon quantum dots as antimicrobial agents against gram-positive Bacillus subtilis and Staphylococcus aureus under visible white light-emitting diode

Carbon nanomaterials, such as carbon quantum dots (CQDs), are excellent candidates for antibacterial agent development as they are cost-effective. Nitrogen-doped CQDs (N-doped CQDs) exhibit antibacterial activity against gram-positive bacteria. However, investigation of N-CQDs and their efficacy against the selected bacterial strains under visible light irradiation has not been carried out. Here, we aimed to evaluate N-CQDs for their efficacy as a photosensitizer for antimicrobial photodynamic therapy (aPDT). N-CQDs were synthesized using the hydrothermal method with 1,3,6-trinitropyrene (TNP) as the nitrogen and carbon source. Antimicrobial tests of N-CQDs were conducted against gram-positive (Bacillus subtilis NCIB 3610, Staphylococcus aureus Newman, and S. aureus USA300) and gram-negative (Escherichia coli K12) bacteria at different concentrations (0–100 mg/L). The N-CQDs exerted a moderate growth-inhibitory effect on gram-positive bacteria in the dark. However, in the presence of white light generated using 20-W light-emitting diode, N-CQDs could completely kill the bacteria at a low concentration of 20 mg/L. The minimal inhibitory concentration of N-CQDs for the two S. aureus strains (Newman and USA300) was 20 mg/L under light conditions, whereas that for B. subtilis was 100 mg/L. The results demonstrate that N-CQDs may be used as a photosensitizer in aPDT and as an antibacterial agent.

Anti-Lymphangiogenic Terpenoids from the Heartwood of Taiwan Juniper, Juniperus chinensis var. tsukusiensis.

To look in-depth into the phytochemical and pharmacological properties of Taiwan juniper, this study investigated the chemical profiles and anti-lymphangiogenic activity of Juniperus chinensis var. tsukusiensis. In this study, four new sesquiterpenes, 12-acetoxywiddrol (1), cedrol-13-al (2), α-corocalen-15-oic acid (3), 1,3,5-bisaoltrien-10-hydroperoxy-11-ol (4), one new diterpene, 1β,2β-epoxy-9α-hydroxy-8(14),11-totaradiene-3,13-dione (5), and thirty-three known terpenoids were successfully isolated from the heartwood of J. chinensis var. tsukusiensis. The structures of all isolates were determined through the analysis of physical data (including appearance, UV, IR, and optical rotation) and spectroscopic data (including 1D, 2D NMR, and HRESIMS). Thirty-four compounds were evaluated for their anti-lymphangiogenic effects in human lymphatic endothelial cells (LECs). Among them, totarolone (6) displayed the most potent anti-lymphangiogenic activity by suppressing cell growth (IC50 = 6 ± 1 µM) of LECs. Moreover, 3β-hydroxytotarol (7), 7-oxototarol (8), and 1-oxo-3β-hydroxytotarol (9) showed moderate growth-inhibitory effects on LECs with IC50 values of 29 ± 1, 28 ± 1, and 45 ± 2 µM, respectively. Totarolone (6) also induced a significant concentration-dependent inhibition of LEC tube formation (IC50 = 9.3 ± 2.5 µM) without cytotoxicity. The structure-activity relationship discussion of aromatic totarane-type diterpenes against lymphangiogenesis of LECs is also included in this study. Altogether, our findings unveiled the promising potential of J. chinensis var. tsukusiensis in developing therapeutics targeting tumor lymphangiogenesis.

Abstract 1632: MDM2 inhibitor alrizomadlin (APG-115) promotes antitumor activity of mitogen-activated protein kinase (MAPK) inhibitors in uveal melanoma

Abstract Uveal melanoma (UM) is the commonest primary intraocular malignancy, yet its molecular pathogenesis is poorly understood. Most UM cases have activating mutations in genes encoding G protein subunits alpha Q or 11, leading to activation of downstream effectors. These include protein kinase C, mitogen-activated protein kinases (MAPK1/3; also termed extracellular signal-regulated kinase 2/1 [ERK2⁄ERK1], respectively), and yes-associated protein, suggesting a rationale for therapeutically targeting these related pathways. Genetic analyses show that TP53 is infrequently mutated in UM, but associated pathways may be functionally inactivated. Ubiquitination-mediated degradation of p53 activates MAPK signaling, such that, active p53 may promote suppression of MAPK signaling. Alrizomadlin (APG-115) is a small molecule targeting p53/MDM2 that is in clinical development for solid and hematologic cancers. This study evaluated the antitumor effect of alrizomadlin, alone or combined with other targeted therapies, in preclinical models of UM. In cell-based antiproliferation assays of many UM cell lines, alrizomadlin exerted moderate growth inhibitory effects (IC50 = 0.151-1.857μM). When combined with inhibitors against mitogen-activated protein kinase kinase (MEK) [trametinib and selumetinib], mammalian target of rapamycin (mTOR) [rapamycin], focal adhesion kinase (FAK) [defactinib and Ascentage’s APG-2449, which targets FAK/ALK/ROS1], and MEK/rapidly accelerated fibrosarcoma [RAF] [VS-6766], alrizomadlin demonstrated enhanced antiproliferative activity. In a UM xenograft model (MP41), alrizomadlin showed dose-dependent antitumor activity when administered at 25, 50, and 100 mg/kg, with tumor growth inhibition (TGI) rates of 24.8%, 38%, and 39.1%, respectively. In this model, synergistic antitumor effects were observed when alrizomadlin was combined with selumetinib or APG-2449, with TGI rates of 65.4% and 47.5%, respectively. Mechanistically, alrizomadlin likely increased p53, MDM2, and downstream p21 in MP41 cells. Importantly, alrizomadlin inhibited ERK phosphorylation and enhanced selumetinib inhibition in a dose- and time-dependent manner. Prior studies indicated that FAK can suppress p53 by enhancing MDM2-dependent p53 ubiquitination. In this study, APG-2449 showed dose-dependent inhibition of FAK phosphorylation and upregulation of p53. Alrizomadlin also inhibited phosphorylation of FAK and downstream ERK. Therefore, the combination of alrizomadlin and APG-2449 was synergistic. Combining MEK and FAK inhibitors also markedly augmented caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1) cleavage (apoptosis hallmarks) and enhanced observed antitumor effects. In conclusion, our results demonstrate the potential utility of combining alrizomadlin with MAPK pathway inhibitors to treat patients with UM. Citation Format: Guangfeng Wang, Eric Liang, Ping Min, Dajun Yang, Yifan Zhai. MDM2 inhibitor alrizomadlin (APG-115) promotes antitumor activity of mitogen-activated protein kinase (MAPK) inhibitors in uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1632.

Abstract P4-01-17: Preventing adaptive therapeutic resistance to CDK4/6 inhibition with CDK8/19 inhibitors

Abstract Inhibitors of CDK4/6 have provided a major addition to the clinical armamentarium in estrogen receptor (ER)-positive breast cancers. Palbociclib and other FDA-approved CDK4/6 inhibitors slow down tumor growth and induce senescence (irreversible cell cycle arrest) by inhibiting downstream phosphorylation of the Rb protein by the CDK4/6-Cyclin D complex. However, long-term treatment with CDK4/6 inhibitors inevitably leads to drug resistance and an overall decline in drug efficacy, both in laboratory models and in the clinic. Therefore, identifying an approach to preventing the development of resistance to CDK4/6 inhibitors would be beneficial to improving patient outcomes.CDK8 or its isoform, CDK19, together with their binding partner Cyclin C (CCNC) and proteins MED12 and MED13, form the regulatory CDK module of the transcriptional Mediator complex. CDK8/19 are actively pursued drug targets, with highly selective pharmacological inhibitors of CDK8/19 becoming available. The primary function of CDK8/19 Mediator kinase is potentiation of several signal-responsive transcription factors, such as ER, NFκB, SMADs, STATs and HIF1α; CDK8/19 inhibition suppresses signal-induced expression of a subset of genes activated by such transcription factors. This function defines CDK8/19 as mediators of transcriptional reprogramming, a critical process for the development of drug resistance, and CDK8/19 inhibition has been found to prevent the development of resistance to several classes of anticancer drugs. We have now tested if selective CDK8/19 inhibitors, Senexin B and SNX631, could prevent the development of Palbociclib resistance in ER-positive breast cancers. Our experiments have shown that Palbociclib-treated ER-positive breast cell lines, when cultured in the presence of Palbociclib, rapidly become resistant. CDK8/19 inhibitors have only a moderate growth-inhibitory effect in these cells and do not overcome acquired Palbociclib resistance. However, when CDK8/19 inhibitors are added together with Palbociclib, resistance does not develop. We have found that CDK8/19 inhibitors counteract some of the transcriptomic effects of Palbociclib and interact with this drug in modulating Rb expression and phosphorylation and attenuating the senescent phenotype. These results suggest specific mechanisms through which CDK8/19 inhibition prevents the development of adaptive resistance to Palbociclib. These in vitro findings are currently being investigated in vivo in an ER-positive breast cancer xenograft model. Citation Format: Zachary Mack, Margarita Yastrebova, Alvina Khamidullina, Amanda Sharko, Xiaokai Ding, Stephan Bowe, Nikitha Sashi, Samantha Safa, Kaitlyn Digsby, Amanda Eckstrom, Vitali Sikirzhitski, Chang-uk Lim, Victor Tatarskiy, Igor Roninson, Eugenia Broude. Preventing adaptive therapeutic resistance to CDK4/6 inhibition with CDK8/19 inhibitors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-01-17.

Straightforward synthesis of novel spiroether derivatives

We report the first full synthesis of novel spiroether derivatives via reaction of 4-oxobut-2-enoates and alloxan. Our synthesis features the single-step assembly, mild reaction conditions, good yields, high diastereoselectivity, operational simplicity, and the absence of tedious separation procedures. Most of the prepared compounds possessed moderate growth inhibitory effects on human alveolar adenocarcinoma (A549), malignant melanoma (A375), ovarian adenocarcinoma (SK-OV-3), and fibrosarcoma (HT-1080) cell lines.

Identification of the Biosynthetic Gene Cluster of Thermoactinoamides and Discovery of New Congeners by Integrated Genome Mining and MS-Based Molecular Networking.

The putative non-ribosomal peptide synthetase (NRPS) gene cluster encoding the biosynthesis of the bioactive cyclohexapeptide thermoactinoamide A (1) was identified in Thermoactinomyces vulgaris DSM 43016. Based on an in silico prediction, the biosynthetic operon was shown to contain two trimodular NRPSs, designated as ThdA and ThdB, respectively. Chemical analysis of a bacterial crude extract showed the presence of thermoactinoamide A (1), thereby supporting this biosynthetic hypothesis. Notably, integrating genome mining with a LC-HRMS/MS molecular networking-based investigation of the microbial metabolome, we succeeded in the identification of 10 structural variants (2–11) of thermoactinoamide A (1), five of them being new compounds (thermoactinoamides G-K, 7–11). As only one thermoactinoamide operon was found in T. vulgaris, it can be assumed that all thermoactinoamide congeners are assembled by the same multimodular NRPS system. In light of these findings, we suggest that the thermoactinoamide synthetase is able to create chemical diversity, combining the relaxed substrate selectivity of some adenylation domains with the iterative and/or alternative use of specific modules. In the frame of our screening program to discover antitumor natural products, thermoactinoamide A (1) was shown to exert a moderate growth-inhibitory effect in BxPC-3 cancer cells in the low micromolar range, while being inactive in PANC-1 and 3AB-OS solid tumor models.

Lithocarols A-F, six tenellone derivatives from the deep-sea derived fungus Phomopsis lithocarpus FS508

Lithocarols A-F (1–6) possessing novel highly-oxygenated isobenzofuran core, together with a related known compound isoprenylisobenzofuran A (7) were isolated from the marine-derived fungus Phomopsis lithocarpus FS508. Among them, lithocarols A-E (1–5) represent the first examples of poly-ketal derivatives in tenellone family. The structures for all these compounds were fully elucidated by spectroscopic analysis, X-ray diffraction, and electronic circular dichroism calculations. Their cytotoxic assay disclosed that compounds 1–4 displayed moderate growth inhibitory effect against four human tumor cell lines with the IC50 values ranging from 10.5 to 38.7 μM.

An ethnobotanical survey and in vitro cytotoxicity study of medicinal plants traditionally used in the treatment of cancers in Ugbine, Nigeria

An ethnobotanical survey and in vitro cytotoxicity study of medicinal plants traditionally used in the treatment of cancers in Ugbine, Nigeria

Study on the structures and anti-hepatic fibrosis activity of stilbenoids from Arundina graminifolia (D. Don) Hochr.

A phytochemical study was performed on Arundina graminifolia (D.Don) Hochr. by silica gel column and semi-preparative HPLC, and ten stilbenoids were obtained. Their structures were elucidated by NMR and MS spectra and identified as 7-hydroxy-2,4-dimethoxy-9,10-dihydrophenanthrene (1), 4,7-dihydroxy-2-methoxy-9,10-dihydrophenanthrene (2), 2,7-dihydroxy-4-methoxy-9,10-dihydrophenanthrene (3), 3,3’-dihydroxy-5-methoxy-bibenzyl (4), 7-hydroxy-2,8-dimethoxy-phenanthrene-1,4-dione (5), 7-hydroxy-2,10-dimethoxy-phenanthre-ne-1,4-dione (6), 7-dihydroxy-2-methoxy-9,10-dihydrophenanthrene-1,4-dione (7), 7-hydroxy-2-methoxy-phenanthrene-1,4-dione (8), 7-hydroxy-1-(p-hydroxybenzyl)-2,4-dimethoxy-9,10-dihydroxy-phenanthrene (9), 2,7-dihydroxy-1-(p-hydroxybenzyl)-4-methoxy-9,10-dihydroxy-phenanthrene (10). Compounds 5 and 6 were isolated from this plant for the first time. The isolated compounds were examined for their anti-hepatic fibrosis activity against HSC-T6 cells in vitro. The results showed that compounds 4 and 5 exhibited moderate growth inhibitory effects with IC50 61.9 μg/mL and 52.7 μg/mL, respectively.

Dihydroartemisinin Sensitizes Human Lung Adenocarcinoma A549 Cells to Arsenic Trioxide via Apoptosis.

Recent studies have shown that arsenic trioxide (ATO) is an effective anti-cancer drug for treatment of acute promyelocytic leukemia and other types of human cancer. However, we have found that lung cancer cells constantly develop a high level of resistance to ATO. In this study, we have explored a possibility of combination of dihydroartemisinin (DHA) and ATO treatments to reduce ATO resistance of lung cancer cells. We determined the combinatory effects of DHA and ATO on cytotoxicity of human lung adenocarcinoma (A549) cells. We showed that co-exposure to DHA and ATO of A549 cells synergistically increased the cytotoxicity and apoptotic cell death in the cells. We found that the synergistic effect of DHA and ATO in promoting apoptosis mainly resulted from increased cellular level of reactive oxygen species (ROS) and DNA damage. ATO alone only exerted moderate growth inhibitory effects on A549 cells. The results indicate that DHA can significantly sensitize ATO-induced cytotoxicity of A549 lung cancer cells through apoptosis mediated by ROS-induced DNA damage. Interestingly, we found that the combinatory treatment of DHA and ATO did not result in significant adverse effects in normal human bronchial epithelial (HBE) cells. Our results further provide evidence for the potential application of combinatory effects of DHA and ATO as a safe therapy for human lung cancer.

SYNTHESIS, BIOLOGICAL EVALUATION AND BINDING STUDIES OF NEW FLAVONE DERIVATIVES AS ADENOSINE A2B RECEPTOR ANTAGONISTS

A series of eleven flavone derivatives were synthesized. The synthesized compounds were characterized structurally by various techniques using spectral analyses. All of the synthesized compounds were subjected to MTT proliferation assay to investigate their in-vitro cytotoxic activity. Among all the studied compounds, compounds, VIi, VIh, VId and VIk revealed moderate growth inhibitory effect towards the MDA-MB 231 cell line compared to the reference, doxorubicin. These compounds showed cytotoxicity activity with IC50 values ranging from 43.7 to 138 µM in MDA-MB 231 cell line. The results of cytotoxic activity revealed that flavone derivatives with N-aryl acetamide substituted at the 3-position of flavone backbone have better cytotoxic activity. Moreover, the highest activity was observed with compound VIi that has oxy-N-pyriden-2-yl acetamide substituent at the 3-position of flavone backbone followed by compound VIh with IC50 values of 43.7 and 50 μM, respectively. The biological activity results were elucidated by molecular docking studies using the homology model of the human adenosine A2B receptor. As a result, the present study has highlighted that the bicyclic moiety of the compounds attached to hydrogen bond donor-acceptor capability and π-π stacking is an attractive scaffold for obtaining cytotoxic activity.

Structural Diversity of New C13-Polyketides Produced by Chaetomium mollipilium Cultivated in the Presence of a NAD+-Dependent Histone Deacetylase Inhibitor

Cultivation of Chaetomium mollipilium with nicotinamide, a NAD(+)-dependent HDAC inhibitor, stimulated its secondary metabolism, leading to the isolation of structurally diverse new C(13)-polyketides, mollipilin A-E (1-5) as well as two known compounds (6 and 7). Spectroscopic methods, X-ray single crystal diffraction analysis, and VCD elucidated the absolute configurations of structures 1-6, and plausible biosynthetic pathways for 1-7 were proposed based on structural relationships. Mollipilins A (1) and B (2) exhibited moderate growth inhibitory effects on HCT-116 cells.

Effects of Pesticides on the Bacterial Production of Pyrrolnitrin

Pyrrolnitrin is a halogenated bacterial metabolite with antifungal and antibacterial activities which served as a lead structure of synthetic fungicides. Several pyrrolnitrin-producing bacteria are considered to be promising biopesticides. However, the application of these microorganisms is not straightforward since many synthetic pesticides usually coexist in agricultural fields and inevitably affect the efficacy of biocontrol agents. In this regard, effects of 25 xenobiotics, including 18 pesticides, were investigated for pyrrolnitrin biosynthesis by Burkholderia sp. O33 and Pseudomonas fluorescens Pf-5. Strong inhibition of pyrrolnitrin synthesis was observed in 9 chemicals, including 6 pesticides, while glyphosate and validamycin enhance biosynthesis. Fenpiclonil and fludioxonil strongly inhibit the oxidative transformation of aminopyrrolnitrin to pyrrolnitrin. Halogenation reaction to aminopyrrolnitrin was reduced by methimazole, a well-known flavin-dependent monooxygenase inhibitor. Most pesticides gave moderate growth inhibitory effects. The results suggested that synthetic chemicals can modulate the efficacy of pyrrolnitrin producing bacteria, through the inhibition of cell growth or pyrrolnitrin biosynthesis. Pathway specific inhibition by fenpiclonil, fludioxonil, and methimazole will give structural insights of corresponding enzymes.

Antimicrobial sensitivity of Escherichia coli to alumina nanoparticles

Metal oxide nanoparticles (NPs) are known to possess strong antimicrobial properties. Aluminum oxide NPs have wide-range applications in industrial as well as personal care products. In the absence of prior reports on the antimicrobial properties of alumina NPs for a wide concentration range, the principal objective of the present work was to study the growth-inhibitory effect of alumina NPs over a wide concentration range (10–1000 μg/mL) on an environmentally relevant gram-negative model microorganism, Escherichia coli. The mean diameter of the NPs was determined to be 179 nm in aqueous dispersion used for this study, and surface area was determined to be 21.23 m 2/g. The concentration of 1000 μg/mL was found to be moderately inhibitory for bacteria. Almost negligible dependence of growth rate on the concentration of the NPs was observed. The extracellular protein content was found to be slightly lower in case of cells interacting with 1000 μg/mL alumina than the uninteracted control cells. Fourier transform–infrared studies established differences in structure between interacted and uninteracted cells. Alumina NPs showed a mild growth-inhibitory effect, only at very high concentrations, which might be due to surface charge interactions between the particles and cells. Free-radical scavenging properties of the particles might have prevented cell wall disruption and drastic antimicrobial action. This laboratory-scale study suggests that alumina NPs may only exhibit mild toxicity toward microorganisms in the environment. From the Clinical Editor Metal oxide NPs, inluding aluminum oxide NPs, are known to possess strong antimicrobial properties. The study demonstrated a mild to moderate growth-inhibitory effect of alumina NPs over a wide concentration range (10-1000 μg/mL) on Escherichia coli. Almost negligible dependence on the concentration was observed.

Tumor-Suppressor Function of SPARC-Like Protein 1/Hevin in Pancreatic Cancer

SPARC-like protein 1 (SPARCL1), a member of the SPARC family, is downregulated in various tumors. In the present study, the expression and localization of SPARCL1 were analyzed in a wide range of nontumorous and neoplastic pancreatic tissues by quantitative reverse transcription-polymerase chain reaction, laser capture microdissection, microarray analysis, and immunohistochemistry. For functional analysis, proliferation and invasion assays were used in cultured pancreatic cancer cells. Pancreatic ductal adenocarcinoma (PDAC) and other pancreatic neoplasms exhibited increased SPARCL1 mRNA levels compared to those of the normal pancreas. SPARCL1 mRNA levels were low to absent in microdissected and cultured pancreatic cancer cells, and promoter demethylation increased SPARCL1 levels only slightly in three of eight cell lines. SPARCL1 was observed in small capillaries in areas of inflammation/tumor growth and in some islet cells. In PDAC, 15.4% of vessels were SPARCL1-positive. In contrast, the percentage of SPARCL1-positive vessels was higher in chronic pancreatitis and benign and borderline pancreatic tumors. Recombinant SPARCL1 inhibited pancreatic cancer cell invasion and exerted moderate growth-inhibitory effects. In conclusion, SPARCL1 expression in pancreatic tissues is highly correlated with level of vascularity. Its antiinvasive effects and reduced expression in metastasis indicate tumor-suppressor function.

Three new jatrophane-type diterpenes from Euphorbia pubescens.

Three new macrocyclic jatrophane diterpene polyesters, named pubescenes A ( 1), B ( 2), and C ( 3), and the known compounds indole-3-aldehyde and scopoletin have been isolated and characterised from the whole dried plant of Euphorbia pubescens. The structures of the new compounds were established by spectroscopic means including 2D-NMR techniques such as COSY, HMQC, HMBC and NOESY experiments. Compounds 1 - 3 were evaluated for their in vitro effect on the growth of three human cancer cell lines MCF-7 (breast), NCI-H460 (lung) and SF-268 (CNS) as well as for their capacity to interfere with the proliferation of human peripheral blood lymphocytes. They exhibited a moderate growth inhibitory effect on the cancer cell line NCI-H460. No effect was observed on the mitogenic response of human lymphocytes to PHA.

Synthetic Nucleosides and Nucleotides. 40. Selective Inhibition of Eukaryotic DNA Polymerase α by 9-(β-D-Arabinofuranosyl)-2-(p-n-butylanilino)adenine 5′-Triphosphate (BuAaraATP) and Its 2′-Up Azido Analog: Synthesis and Enzymatic Evaluations†

Starting from 2′,3′,5′-tri-O-acetyl-2-iodoadenosine, 9-(β-D-arabinofuranosyl)-2-(p-n-butylanilino)adenine and its 2′(S)-azido counterparts were synthesized in seven steps. These exhibited only moderate growth-inhibitory effects against mouse leukemic P388 cells (IC50 = 13–24 μM), although 5′-triphosphate derivatives showed strong and selective inhibitory action on calf thymus DNA polymerase α, but not on β- and ϵ-polymerases from eukaryotes. This paper is dedicated to the memory of Professor Tsujiaki Hata

Growth inhibition of human lung adenocarcinoma cells by antibodies against epidermal growth factor receptor and by ganglioside GM3: involvement of receptor-directed protein tyrosine phosphatase(s).

Growth of the EGF receptor-expressing non-small-cell lung carcinoma cell line H125 seems to be at least partially driven by autocrine activation of the resident EGF receptors. Thus, the possibility of an EGF receptor-directed antiproliferative treatment was investigated in vitro using a monoclonal antibody (alpha EGFR ior egf/r3) against the human EGF receptor and gangliosides which are known to possess antiproliferative and anti-tyrosine kinase activity. The moderate growth-inhibitory effect of alpha EGFR ior egf/r3 was strongly potentiated by the addition of monosialoganglioside GM3. Likewise, the combination of alpha EGFR ior egf/r3 and GM3 inhibited EGF receptor autophosphorylation activity in H125 cells more strongly than either agent alone. A synergistic inhibition of EGF receptor autophosphorylation by alpha EGFR ior egf/r3 and GM3 was also observed in the human epidermoid carcinoma cell line A431. In both cell lines, the inhibition of EGF receptor autophosphorylation by GM3 was prevented by pretreatment of the cells with pervanadate, a potent inhibitor of protein tyrosine phosphatases (PTPases). Also, GM3 accelerated EGF receptor dephosphorylation in isolated A431 cell membranes. These findings indicate that GM3 has the capacity to activate EGF receptor-directed PTPase activity and suggest a novel possible mechanism for the regulation of cellular PTPases.

Chemical and biochemical studies on carbohydrate esters. IX. Antitumor effects of selectively fatty acylated products of maltose.

Selective fatty acylation of maltose was carried out by heating an equimolar mixture of the disaccharide and an appropriate acid chloride in pyridine. The resulting crude product was chromatographed to furnish two preparations, termed maltose-[mono]- and-[high]-esters ; the former preparation was an isomeric mixture of monoesters among which the 1-, 6-, and 6'-isomers were presumably predominant, and the latter consisted of di-, tri-, and poly-esters, as indicated by gas-liquid and thin-layer chromatographies. The antitumor effects of the maltose-[mono]-esters of stearic, palmitic, myristic, lauric, and caprylic acids towards Ehrlich ascites carcinoma in mice were tested by the total packed cell volume method, by intraperitoneal injection. The stearic, palmitic, and myristic esters proved to be effective, while the lauric and caprylic esters exhibited a slight effect and no effect, respectively. The antitumor effect of the maltose-[mono]-stearate upon the same tumor was compared with that of the analogous derivative of sucrose by survival bioassay (intraperitoneal administration) at various doses. Both compounds showed similar antitumor results, giving especially marked effects at the dose of 50 mg/kg/day×5. These two compounds also exerted moderate growth-inhibitory effects against solid sarcoma 180 in mice when they were administered subcutaneously ; in the case of sucrose-[mono]-stearate, intramuscular injection was also effective. The maltose-[high]-esters of stearic, palmitic, and myristic acids failed to exert marked activity upon this solid tumor by either administration route.