Synthesis and biological evaluation of carbon-substituted C-4 derivatives of podophyllotoxin

Several C-4 carbon-substituted analogues of podophyllotoxin, 1, were prepared by treatment of 1 with allyltrimethylsilane or trimethylsilylcyanide in the presence of boron trifluoride etherate. Alternatively, carbon substituents were introduced via additions to the carbobenzyloxy-protected C-4′-dimethylated podophyllotoxone. These 4′-dimethylated derivatives showed promising in vitro antitumour activity and were equally active against human colon cell line HT116 and two multidrug resistant cell lines. The alcohol 6 was evaluated in vivo but was found to be inactive. Key words: podophyllotoxin analogues, podophyllotox-4-one, C4 carbon substituted podophyllotoxins.

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Overcoming multidrug-resistance in vitro and in vivo using the novel P-glycoprotein inhibitor 1416

Bioscience Reports ◽

10.1042/bsr20120020 ◽

2012 ◽

Vol 32 (6) ◽

pp. 559-566 ◽

Cited By ~ 19

Author(s):

Yan Xu ◽

Feng Zhi ◽

Guangming Xu ◽

Xiaolei Tang ◽

Sheng Lu ◽

...

Keyword(s):

Multidrug Resistance ◽

Cancer Chemotherapy ◽

Antitumour Activity ◽

Multidrug Resistant ◽

The Novel ◽

Mice Model ◽

P Glycoprotein ◽

Channel Currents

MDR (multidrug-resistance) represents a major obstacle to successful cancer chemotherapy and is usually accomplished by overexpression of P-gp (P-glycoprotein). Much effort has been devoted to developing P-gp inhibitors to modulate MDR. However, none of the inhibitors on the market have been successful. 1416 [1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (phenoprolamine hydrochloride)] is a new VER (verapamil) analogue with a higher IC50 for blocking calcium channel currents than VER. In the present paper, we examined the inhibition effect of 1416 on P-gp both in vitro and in vivo. 1416 significantly enhanced cytotoxicity of VBL (vinblastine) in P-gp-overexpressed human multidrug-resistant K562/ADM (adriamycin) and KBV cells, but had no such effect on the parent K562 and KB cells. The MDR-modulating function of 1416 was further confirmed by increasing intracellular Rh123 (rhodanmine123) content in MDR cells. Human K562/ADM xenograft-nude mice model verified that 1416 potentiates the antitumour activity of VBL in vivo. RT-PCR (reverse transcriptase-PCR) and FACS analysis demonstrated that the expression of MDR1/P-gp was not affected by 1416 treatment. All these observations suggest that 1416 could be a promising agent for overcoming MDR in cancer chemotherapy.

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Arabinoxylan-Based Particles: In Vitro Antioxidant Capacity and Cytotoxicity on a Human Colon Cell Line

Medicina ◽

10.3390/medicina55070349 ◽

2019 ◽

Vol 55 (7) ◽

pp. 349 ◽

Cited By ~ 2

Author(s):

Mayra A. Mendez-Encinas ◽

Elizabeth Carvajal-Millan ◽

Agustín Rascón-Chu ◽

Humberto Astiazarán-García ◽

Dora E. Valencia-Rivera ◽

...

Keyword(s):

Antioxidant Activity ◽

Antioxidant Capacity ◽

Cell Line ◽

Human Colon ◽

Colon Cells ◽

Antioxidant Power ◽

Human Colon Cell Line ◽

Colon Cell ◽

Colon Cell Line

Background and objectives: Arabinoxylans (AX) can gel and exhibit antioxidant capacity. Previous studies have demonstrated the potential application of AX microspheres as colon-targeted drug carriers. However, the cytotoxicity of AX gels has not been investigated so far. Therefore, the aim of the present study was to prepare AX-based particles (AXM) by coaxial electrospraying method and to investigate their antioxidant potential and cytotoxicity on human colon cells. Materials and Methods: The gelation of AX was studied by monitoring the storage (G′) and loss (G′′) moduli. The morphology of AXM was evaluated using optical and scanning electron microscopy (SEM). The in vitro antioxidant activity of AX before and after gelation was measured using the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+), 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) methods. In addition, the effect of AX and AXM on the proliferation of human colon cells (CCD 841 CoN) was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Results: The final G′ and G′′ values for AX gels were 293 and 0.31 Pa, respectively. AXM presented spherical shape and rough surface with a three-dimensional and porous network. The swelling ratio and mesh size of AXM were 35 g water/g AX and 27 nm, respectively. Gelation decreased the antioxidant activity of AX by 61–64 %. AX and AXM did not affect proliferation or show any toxic effect on the normal human colon cell line CCD 841 CoN. Conclusion: The results indicate that AXM could be promising biocompatible materials with antioxidant activity.

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Design, Synthesis and In-Vitro Biological Evaluation of Antofine and Tylophorine Prodrugs as Hypoxia-Targeted Anticancer Agents

Molecules ◽

10.3390/molecules26113327 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3327

Author(s):

Ziad Omran ◽

Chris P. Guise ◽

Linwei Chen ◽

Cyril Rauch ◽

Ashraf N. Abdalla ◽

...

Keyword(s):

Anticancer Agents ◽

Biological Activities ◽

Multidrug Resistant ◽

Biological Evaluation ◽

High Chemical ◽

Design Synthesis ◽

Hypoxic Conditions ◽

Cancerous Cell

Phenanthroindolizidines, such as antofine and tylophorine, are a family of natural alkaloids isolated from different species of Asclepiadaceas. They are characterized by interesting biological activities, such as pronounced cytotoxicity against different human cancerous cell lines, including multidrug-resistant examples. Nonetheless, these derivatives are associated with severe neurotoxicity and loss of in vivo activity due to the highly lipophilic nature of the alkaloids. Here, we describe the development of highly polar prodrugs of antofine and tylophorine as hypoxia-targeted prodrugs. The developed quaternary ammonium salts of phenanthroindolizidines showed high chemical and metabolic stability and are predicted to have no penetration through the blood–brain barrier. The designed prodrugs displayed decreased cytotoxicity when tested under normoxic conditions. However, their cytotoxic activity considerably increased when tested under hypoxic conditions.

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Synthesis and Biological Evaluation of RGD–Cryptophycin Conjugates for Targeted Drug Delivery

Pharmaceutics ◽

10.3390/pharmaceutics11040151 ◽

2019 ◽

Vol 11 (4) ◽

pp. 151 ◽

Cited By ~ 9

Author(s):

Adina Borbély ◽

Eduard Figueras ◽

Ana Martins ◽

Simone Esposito ◽

Giulio Auciello ◽

...

Keyword(s):

Drug Delivery ◽

Cell Lines ◽

Parent Compound ◽

Integrin Αvβ3 ◽

Multidrug Resistant ◽

Biological Evaluation ◽

Improved Stability ◽

Cryptophycin 52

Cryptophycins are potent tubulin polymerization inhibitors with picomolar antiproliferative potency in vitro and activity against multidrug-resistant (MDR) cancer cells. Because of neurotoxic side effects and limited efficacy in vivo, cryptophycin-52 failed as a clinical candidate in cancer treatment. However, this class of compounds has emerged as attractive payloads for tumor-targeting applications. In this study, cryptophycin was conjugated to the cyclopeptide c(RGDfK), targeting integrin αvβ3, across the protease-cleavable Val-Cit linker and two different self-immolative spacers. Plasma metabolic stability studies in vitro showed that our selected payload displays an improved stability compared to the parent compound, while the stability of the conjugates is strongly influenced by the self-immolative moiety. Cathepsin B cleavage assays revealed that modifications in the linker lead to different drug release profiles. Antiproliferative effects of Arg-Gly-Asp (RGD)–cryptophycin conjugates were evaluated on M21 and M21-L human melanoma cell lines. The low nanomolar in vitro activity of the novel conjugates was associated with inferior selectivity for cell lines with different integrin αvβ3 expression levels. To elucidate the drug delivery process, cryptophycin was replaced by an infrared dye and the obtained conjugates were studied by confocal microscopy.

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Imidazole Analogs of Vascular-Disrupting Combretastatin A-4 with Pleiotropic Efficacy against Resistant Colorectal Cancer Models

International Journal of Molecular Sciences ◽

10.3390/ijms222313082 ◽

2021 ◽

Vol 22 (23) ◽

pp. 13082

Author(s):

Franziska Reipsch ◽

Bernhard Biersack ◽

Henrike Lucas ◽

Rainer Schobert ◽

Thomas Mueller

Keyword(s):

Colorectal Cancer ◽

Cell Lines ◽

Multidrug Resistant ◽

Resistant Cell ◽

Antitumor Effects ◽

Metastasis Model ◽

Main Representative ◽

Vascular Disrupting

Specific targeting of the tumoral vasculature by vascular-disrupting agents (VDA), of which combretastatin A-4 (CA-4) is a main representative, has been considered a new therapeutic strategy against multidrug-resistant tumors. In addition, CA-4 and analogs are tubulin-targeting agents and can exert direct antitumor effects by different mechanisms. Herein, we analyzed a series of synthetic CA-4 analogs featuring N-methylimidazole-bridged Z-alkenes with different halo- or amino-substituted aryl rings in vitro and in vivo, focusing on models of colorectal cancer. Combined in vitro/in vivo structure–activity relationship studies using cell lines and xenograft tumors susceptible to VDA-induced vascular damage demonstrated a clear association of cytotoxic and vascular-disrupting activity with the ability to inhibit tubulin polymerization, which was determined by specific substitution constellations. The most active compounds were tested in an extended panel of colorectal cancer (CRC) cell lines and showed activity in CA-4-resistant and chemotherapy-resistant cell lines. The bromo derivative brimamin was then compared with the known fosbretabulin (CA-4P) by activity tests on DLD-1- (multidrug-resistant) and HT29- (CA-4-resistant) derived xenograft tumors. Treatment did not induce pronounced vascular-disrupting effects in these tumors. Histological analyses revealed distinct tumor substructures and vessel compositions of DLD-1/HT29 tumors, which clearly differed from the tumor models susceptible to VDA treatment. Even so, brimamin effectively retarded the growth of DLD-1 tumors, overcoming their resistance to standard treatment, and it inhibited the outgrowth of disseminated HT29 tumor cells in an experimental metastasis model. In conclusion, combretastatin analogous N-methylimidazoles proved capable of inducing vascular-disrupting effects, comparable to those of CA-4P. In addition, they showed antitumor activities in models of drug-resistant colorectal cancer, independent of vascular-disrupting effects.

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Ultrastructural Study of a differentiating human colon carcinoma cell line

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100158583 ◽

1990 ◽

Vol 48 (3) ◽

pp. 208-209

Author(s):

Sylvie Polak-Charcon ◽

Mehrdad Hekmati ◽

Yehuda Ben Shaul

Keyword(s):

Cell Line ◽

Morphological Changes ◽

Secretory Granules ◽

Human Colon ◽

Cell Types ◽

Culture Conditions ◽

Morphological Evidence ◽

Human Colon Carcinoma Cell ◽

Colon Cell

The epithelium of normal human colon mucosa “in vivo” exhibits a gradual pattern of differentiation as undifferentiated stem cells from the base of the crypt of “lieberkuhn” rapidly divide, differentiate and migrate toward the free surface. The major differentiated cell type of the intestine observed are: absorptive cells displaying brush border, goblet cells containing mucous granules, Paneth and endocrine cells containing dense secretory granules. These different cell types are also found in the intestine of the 13-14 week old embryo.We present here morphological evidence showing that HT29, an adenocarcinoma of the human colon cell line, can differentiate into various cell types by changing the growth and culture conditions and mimic morphological changes found during development of the intestine in the human embryo.HT29 cells grown in tissue-culture dishes in DMEM and 10% FCS form at late confluence a multilayer of morphologically undifferentiated cell culture covered with irregular microvilli, and devoid of tight junctions (Figs 1-3).

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In Vitro and in Vivo Comparison of Binding of 99m-Tc-Iabeled Anti-CEA MAb F33-104 with 99m-Tc-labeled Anti-CEA MAb BW431/26

Nuklearmedizin ◽

10.1055/s-0038-1632202 ◽

1999 ◽

Vol 38 (04) ◽

pp. 115-119

Author(s):

N. Oriuchi ◽

S. Sugiyama ◽

M. Kuroki ◽

Y. Matsuoka ◽

S. Tanada ◽

...

Keyword(s):

Nude Mice ◽

Binding Capacity ◽

Colon Adenocarcinoma ◽

Human Colon ◽

Cell Binding ◽

Vitro Binding ◽

Labeling Method ◽

Human Colon Adenocarcinoma

Summary Aim: The purpose of this study was to assess the potential for radioimmunodetection (RAID) of murine anti-carcinoembryonic antigen (CEA) monoclonal antibody (MAb) F33-104 labeled with technetium-99m (99m-Tc) by a reduction-mediated labeling method. Methods: The binding capacity of 99m-Tc-labeled anti-CEA MAb F33-104 with CEA by means of in vitro procedures such as immunoradiometric assay and cell binding assay and the biodistribution of 99m-Tc-labeled anti-CEA MAb F33-104 in normal nude mice and nude mice bearing human colon adenocarcinoma LS180 tumor were investigated and compared with 99m-Tc-labeled anti-CEA MAb BW431/26. Results: The in vitro binding rate of 99m-Tc-labeled anti-CEA MAb F33-104 with CEA in solution and attached to the cell membrane was significantly higher than 99m-Tclabeled anti-CEA MAb BW431/261 (31.4 ± 0.95% vs. 11.9 ± 0.55% at 100 ng/mL of soluble CEA, 83.5 ± 2.84% vs. 54.0 ± 2.54% at 107 of LS 180 cells). In vivo, accumulation of 99m-Tc-labeled anti-CEA MAb F33-104 was higher at 18 h postinjection than 99m-Tc-labeled anti-CEA MAb BW431/26 (20.1 ± 3.50% ID/g vs. 14.4 ± 3.30% ID/g). 99m-Tcactivity in the kidneys of nude mice bearing tumor was higher at 18 h postinjection than at 3 h (12.8 ± 2.10% ID/g vs. 8.01 ± 2.40% ID/g of 99m-Tc-labeled anti-CEA MAb F33-104, 10.7 ± 1.70% ID/g vs. 8.10 ± 1.75% ID/g of 99m-Tc-labeled anti-CEA MAb BW431/26). Conclusion: 99m-Tc-labeled anti-CEA MAb F33-104 is a potential novel agent for RAID of recurrent colorectal cancer.

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Effects of Probiotics in the Management of Infected Chronic Wounds: From Cell Culture to Human Studies

Current Clinical Pharmacology ◽

10.2174/1574884714666191111130630 ◽

2020 ◽

Vol 15 (3) ◽

pp. 193-206

Author(s):

Brognara Lorenzo ◽

Salmaso Luca ◽

Mazzotti Antonio ◽

Di M. Alberto ◽

Faldini Cesare ◽

...

Keyword(s):

Chronic Wounds ◽

Animal Experiments ◽

Multidrug Resistant ◽

Preliminary Evidence ◽

Human Studies ◽

In Vivo Studies ◽

Resistant Bacteria ◽

Keywords Probiotics

Background: Chronic wounds are commonly associated with polymicrobial biofilm infections. In the last years, the extensive use of antibiotics has generated several antibiotic-resistant variants. To overcome this issue, alternative natural treatments have been proposed, including the use of microorganisms like probiotics. The aim of this manuscript was to review current literature concerning the application of probiotics for the treatment of infected chronic wounds. Methods: Relevant articles were searched in the Medline database using PubMed and Scholar, using the keywords “probiotics” and “wound” and “injuries”, “probiotics” and “wound” and “ulcer”, “biofilm” and “probiotics” and “wound”, “biofilm” and “ulcer” and “probiotics”, “biofilm” and “ulcer” and “probiotics”, “probiotics” and “wound”. Results: The research initially included 253 articles. After removal of duplicate studies, and selection according to specific inclusion and exclusion criteria, 19 research articles were included and reviewed, accounting for 12 in vitro, 8 in vivo studies and 2 human studies (three articles dealing with animal experiments included also in vitro testing). Most of the published studies about the effects of probiotics for the treatment of infected chronic wounds reported a partial inhibition of microbial growth, biofilm formation and quorum sensing. Discussion: The application of probiotics represents an intriguing option in the treatment of infected chronic wounds with multidrug-resistant bacteria; however, current results are difficult to compare due to the heterogeneity in methodology, laboratory techniques, and applied clinical protocols. Lactobacillus plantarum currently represents the most studied strain, showing a positive application in burns compared to guideline treatments, and an additional mean in chronic wound infections. Conclusions: Although preliminary evidence supports the use of specific strains of probiotics in certain clinical settings such as infected chronic wounds, large, long-term clinical trials are still lacking, and further research is needed.

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A New Smoothened Antagonist Bearing the Purine Scaffold Shows Antitumour Activity In Vitro and In Vivo

International Journal of Molecular Sciences ◽

10.3390/ijms22168372 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8372

Author(s):

Ana María Zárate ◽

Christian Espinosa-Bustos ◽

Simón Guerrero ◽

Angélica Fierro ◽

Felipe Oyarzún-Ampuero ◽

...

Keyword(s):

Cancer Cells ◽

Human Cancer ◽

Antitumour Activity ◽

Anticancer Compounds ◽

Human Cancer Cells ◽

Cycle Arrest ◽

Apoptosis Inducer ◽

Purine Ring

The Smoothened (SMO) receptor is the most druggable target in the Hedgehog (HH) pathway for anticancer compounds. However, SMO antagonists such as vismodegib rapidly develop drug resistance. In this study, new SMO antagonists having the versatile purine ring as a scaffold were designed, synthesised, and biologically tested to provide an insight to their mechanism of action. Compound 4s was the most active and the best inhibitor of cell growth and selectively cytotoxic to cancer cells. 4s induced cell cycle arrest, apoptosis, a reduction in colony formation and downregulation of PTCH and GLI1 expression. BODIPY-cyclopamine displacement assays confirmed 4s is a SMO antagonist. In vivo, 4s strongly inhibited tumour relapse and metastasis of melanoma cells in mice. In vitro, 4s was more efficient than vismodegib to induce apoptosis in human cancer cells and that might be attributed to its dual ability to function as a SMO antagonist and apoptosis inducer.

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Anticancer Activity of Triazolo-Thiadiazole Derivatives and Inhibition of AKT1 and AKT2 Activation

Pharmaceutics ◽

10.3390/pharmaceutics13040493 ◽

2021 ◽

Vol 13 (4) ◽

pp. 493

Author(s):

Dimitrios T. Trafalis ◽

Sofia Sagredou ◽

Panayiotis Dalezis ◽

Maria Voura ◽

Stella Fountoulaki ◽

...

Keyword(s):

Anticancer Activity ◽

Human Colon ◽

Tumor Xenograft ◽

Atp Binding Site ◽

Anticancer Properties ◽

Extensive Range ◽

Dependent Inhibition ◽

Ht 29

The fusion of 1,2,4-triazole and 1,3,4-thiadiazole rings results in a class of heterocycles compounds with an extensive range of pharmacological properties. A series of 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles was synthesized and tested for its enzyme inhibition potential and anticancer activity. The results show that 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles display potent anticancer properties in vitro against a panel of cancer cells and in vivo efficacy in HT-29 human colon tumor xenograft in CB17 severe combined immunodeficient (SCID) mice. Preliminary mechanistic studies revealed that KA25 and KA39 exhibit time- and concentration-dependent inhibition of Akt Ser-473 phosphorylation. Molecular modeling experiments indicated that 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles bind well to the ATP binding site in Akt1 and Akt2. The low acute toxicity combined with in vitro and in vivo anticancer activity render triazolo[3,4-b]thiadiazoles KA25, KA26, and KA39 promising cancer therapeutic agents.

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