scholarly journals Microtubule Destabilizing Sulfonamides as an Alternative to Taxane-Based Chemotherapy

2021 ◽  
Vol 22 (4) ◽  
pp. 1907
Author(s):  
Myriam González ◽  
María Ovejero-Sánchez ◽  
Alba Vicente-Blázquez ◽  
Raquel Álvarez ◽  
Ana B. Herrero ◽  
...  
Keyword(s):  
Water Solubility ◽  
Aqueous Solubility ◽  
Carcinoma Cells ◽  
Mitotic Catastrophe ◽  
Multi Drug Resistance ◽  
Cervix Carcinoma ◽  
Microtubule Network ◽  
Incidence And Mortality ◽  
High Incidence

Pan-Gyn cancers entail 1 in 5 cancer cases worldwide, breast cancer being the most commonly diagnosed and responsible for most cancer deaths in women. The high incidence and mortality of these malignancies, together with the handicaps of taxanes—first-line treatments—turn the development of alternative therapeutics into an urgency. Taxanes exhibit low water solubility that require formulations that involve side effects. These drugs are often associated with dose-limiting toxicities and with the appearance of multi-drug resistance (MDR). Here, we propose targeting tubulin with compounds directed to the colchicine site, as their smaller size offer pharmacokinetic advantages and make them less prone to MDR efflux. We have prepared 52 new Microtubule Destabilizing Sulfonamides (MDS) that mostly avoid MDR-mediated resistance and with improved aqueous solubility. The most potent compounds, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methylaminobenzenesulfonamide 38, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 42, and N-benzyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 45 show nanomolar antiproliferative potencies against ovarian, breast, and cervix carcinoma cells, similar or even better than paclitaxel. Compounds behave as tubulin-binding agents, causing an evident disruption of the microtubule network, in vitro Tubulin Polymerization Inhibition (TPI), and mitotic catastrophe followed by apoptosis. Our results suggest that these novel MDS may be promising alternatives to taxane-based chemotherapy in chemoresistant Pan-Gyn cancers.

scholarly journals Formulation and Characterization of Felodipine as an Oral Nanoemulsions

2021 ◽  
Vol 30 (1) ◽  
pp. 209-217
Author(s):  
Sumaya B. Hamed ◽  
Shaimaa N. Abd Alhammid
Keyword(s):  
Particle Size ◽  
Oleic Acid ◽  
Zeta Potential ◽  
Water Solubility ◽  
Tween 80 ◽  
Aqueous Solubility ◽  
Compatibility Study ◽  
Drug Content ◽  
Drug Molecules

            Felodipine is a calcium-channel blocker with low aqueous solubility and bioavailability. Lipid dosage forms are attractive delivery systems for such hydrophobic drug molecules. Nanoemulsion (NE) is one of the popular methods that has been used to solve the dispersibility problems of many drugs. Felodipine was formulated as a NE utilizing oleic acid as an oil phase, tween 80 and tween 60 as surfactants and ethanol as a co-surfactant. Eight formulas were prepared, and different tests were performed to ensure the stability of the NEs, such as particle size, polydispersity index, zeta potential, dilution test, drug content, viscosity and in-vitro drug release. Results of characterization showed that felodipine nanoemulsion (F3) with (oleic acid 10%) ,(Smix 60% of tween80 :ethanol in a ratio of 3:1), (DDW 30%) was selected as the best formula, since it has a particle size of (17.01)nm, low PDI (0.392), zeta potential (-22.34mV), good dilution without drug precipitation , higher percent of drug content (99.098%) with  acceptable viscosity , and complete release of the drug after (45 min.) with significantly higher (P<0.05)   dissolution  rate in comparison with the pure drug powder. The selected formula (F3) subjected to further investigations as drug and excipient compatibility study by Fourier transform infrared spectroscopy (FTIR) The outcomes of the (FTIR) explain that the distinctive peaks for felodipine were not affected by other components and displayed the same functional group's band with very slight shifting. This indicates that there was no interaction between felodipine and other NE components. Therefore, these excipients were found to be compatible with felodipine. In conclusion, the NE was found to be an efficient method to enhance the dispersibility and permeatioins of drugs that have poor water solubility (lipophilic drugs).

scholarly journals A N-propionylsulfonamide prodrug of K-5a2 provided improved aqueous solubility and hERG inhibition

2020 ◽  
Author(s):  
Xiaofang Zuo ◽  
Zhipeng Huo ◽  
Dongwei Kang ◽  
Tong Zhao ◽  
Erik De Clercq ◽  
...  
Keyword(s):  
Water Solubility ◽  
Parent Drug ◽  
Aqueous Solubility ◽  
Drug Candidate ◽  
Log P ◽  
Vitro Assay ◽  
Subacute Toxicity ◽  
Anti Hiv ◽  
Hiv 1

Abstract Background Having the potential disadvantages and safety risk of the use of anti-HIV-1 drug candidate K-5a2 in the longterm treatment of HIV patients in mind, we set out with the goal of finding a second-generation backup compound of K-5a2 with the appropriate anti-HIV potency, significantly reduced hERG activity, decreased induction of the CYP enzyme, and improved aqueous solubility. Herein, using a N-propionylsulfonamide prodrug strategy, we report the discovery of compound HM-1Methods In vitro assay of anti-HIV activities in TZM-bl and MT-4 cells, metabolic stability in HLM and human plasma, measurements of water solubility and Log P, assay procedures for hERG activity, acute and subacute toxicity experiment and cytochrome P450 inhibition assay were carried out for HM-1.Results HM-1 can be rapidly hydrolyzed to parent drug K-5a2 and exhibited high potency against HIV-1NL4 − 3 strain (EC50 = 7.99 nM) in TZM-bl cells, HIV-1IIIB strain (EC50 = 2.9 nM) and HIV-1Y181C strain (EC50 = 5.5 nM) in MT-4 cells. And it also showed a > 70-fold improvement in aqueous solubility and presented a low acute toxicity in mice (LD50 > 2 g•kg− 1); no obvious organ damage was detected in the assessment of subacute toxicity. Meanwhile, HM-1 also showed 50 times lower hERG inhibition (IC50 = 6.39 µM) than K-5a2 (IC50 = 0.13 µM).Conclusions It was HM-1 appeared to be free of most of the drawbacks associated with K-5a2 and has been selected for further development as an oral anti-HIV-infection agent.

scholarly journals Cancer Models to Defeat Therapy Resistance in Pancreatic Ductal Adenocarcinoma

2021 ◽  
pp. 43-62
Author(s):  
Britney He
Keyword(s):  
Cancer Research ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Therapy Resistance ◽  
Model Systems ◽  
Ductal Adenocarcinoma ◽  
Multi Drug Resistance ◽  
In Vivo Models ◽  
Incidence And Mortality

One of the largest hurdles to the efficacy of cancer therapeutics, and a main cause of relapse, is therapy resistance. In response, researchers have developed model systems to better understand therapy resistance. Cancer research employs several model systems that reflect the biology of actual human tumors: in vitro models (2D, 3D cell cultures), in vivo models (PDX, GEMMS, transgenic), proteomic models, and computational or mathematical models. One cancer that has been extensively modeled is pancreatic ductal adenocarcinoma (PDAC). PDAC is the third most common cause of annual cancer deaths in developed countries; as its incidence and mortality rates continue to increase, PDAC is projected to be the second leading cause of cancer deaths by 2030. Although chemotherapy is a pillar of clinical PDAC treatment, its outcome typically leads to multi-drug resistance, drastically restricting the curative effect of drugs for a variety of tumors. Elucidating the underlying mechanisms for resistance through different models is essential for the development of new strategies and therapies. This review provides insight into the range of in vitro and in vivo models of pancreatic cancer used in preclinical research. This paper provides an overview of platforms for cancer research with a focus on those devoted to resistance mechanisms in PDAC and to the primary therapeutic intervention for PDAC, gemcitabine (GEM).

In vitro cytotoxic activity of Verbascum alceoides against cervix carcinoma cells

2020 ◽  
Vol 9 (1) ◽  
pp. 19
Author(s):  
Vajihe Akbari ◽  
Masoud Sadeghi Dinani ◽  
Samin Malakooti
Keyword(s):  
Cytotoxic Activity ◽  
Carcinoma Cells ◽  
Cervix Carcinoma

scholarly journals Solubilization Methods for Paclitaxel and Docetaxel: An Overview

2021 ◽  
Author(s):  
Fariba Pourkarim ◽  
Elaheh Rahimpour ◽  
Sima Alvani ◽  
Abolghasem Jouyban
Keyword(s):  
Anticancer Drugs ◽  
Intravenous Infusion ◽  
Water Solubility ◽  
Inclusion Complexation ◽  
Aqueous Solubility ◽  
Micellar Solubilization ◽  
The Past ◽  
The Poor ◽  
High Incidence ◽  
Serious Disease

Cancer is still a serious disease with high incidence over the past decades. Many anticancer drugs are discovered and used to treat cancer, among them, taxanes such as paclitaxel and docetaxel have high lipophilicity and low aqueous solubility which is further magnified considering the strong need for administering them by intravenous infusion. Currently, the poor water-solubility of taxanes is improved by prodrug formation, conjugation, inclusion complexation, micellar solubilization and liposome-based formulations. Recent achievement for solubilization of taxanes are reviewed and critically discussed regarding their pharmaceutical and chemical applications.

Lutein encapsulated oleic - linoleic acid nanoemulsion boosts oral bioavailability of retinal protective carotenoid lutein in rat model

2021 ◽  
Author(s):  
Veeresh B Toragall ◽  
Twinkle Godhwani ◽  
V Baskaran ◽  
Naveen Jayapala
Keyword(s):  
Linoleic Acid ◽  
Oral Bioavailability ◽  
Mixed Micelles ◽  
Water Solubility ◽  
Health Benefits ◽  
Aqueous Solubility ◽  
Mean Size ◽  
The Mean

Abstract There is excessive interest in emerging colloidal delivery systems to enhance the water solubility and oral bioavailability of lutein, which is a hydrophobic carotenoid claimed to possess health benefits. The present study aimed to design lutein-enriched nanoemulsions with improved physicochemical properties and to achieve various health benefits of lutein. The prepared lutein nanoemulsion was characterized, and its bioavailability was examined in vitro (simulated gastrointestinal digestion) and in vivo. The mean size, PDI and zeta potential of the lutein nanoemulsion were 110 ± 8 nm, 0.271 and 36 ± 2 mV, respectively. Furthermore, TEM examination revealed that the particles are nanosized and spherical in shape. Notably, the aqueous solubility of the nanoemulsion was 726-fold higher than that of free lutein. The composite nanoemulsion also showed exceptionally higher (87.4%) in vitro bioaccessibility than that of nonencapsulated or free lutein (15%). The in vivo bioavailability of lutein nanoemulsion (112.6 ng/mL) was much higher than that of nonencapsulated lutein (48.6 ng/ml) and mixed micelles (68.5 ng/mL), and the tissue distribution pattern of lutein nanoemulsion showed higher lutein accumulation in the liver (2.80- and 1.70-fold) and eye (1.91- and 1.48-fold) compared to free lutein and mixed micelle-fed groups. These results suggested that oleic acid-linoleic acid composite nanoemulsions may be a promising delivery system for lutein and may help enhance the solubility, oral bioavailability and bioefficacy of lutein and could be used as an ingredient for the formulation of beverages or functional foods.

scholarly journals Inhibition of UCH-L1 Deubiquitinating Activity with Two Forms of LDN-57444 Has Anti-Invasive Effects in Metastatic Carcinoma Cells

2019 ◽  
Vol 20 (15) ◽  
pp. 3733 ◽  
Author(s):  
Eiji Kobayashi ◽  
Duhyeong Hwang ◽  
Anjali Bheda-Malge ◽  
Christopher B. Whitehurst ◽  
Alexander V. Kabanov ◽  
...  
Keyword(s):  
Cell Lines ◽  
De Novo ◽  
Squamous Carcinoma ◽  
Aqueous Solubility ◽  
Metastatic Carcinoma ◽  
Carcinoma Cells ◽  
Barr Virus ◽  
Squamous Carcinoma Cells ◽  
Invasive Carcinomas

Normally ubiquitin C-terminal hydrolase L1 (UCH-L1) is expressed in the central nervous and reproductive systems of adults, but its de novo expression has been detected in many human cancers. There is a growing body of evidence that UCH-L1 de-ubiquitinating (DUB) activity plays a major pro-metastatic role in certain carcinomas. Here we tested anti-metastatic effects of the small-molecule inhibitor of UCH-L1 DUB activity, LDN-57444, in cell lines from advanced oral squamous cell carcinoma (OSCC) as well as invasive nasopharyngeal (NP) cell lines expressing the major pro-metastatic gene product of Epstein–Barr virus (EBV) tumor virus, LMP1. To overcome the limited aqueous solubility of LDN-57444 we developed a nanoparticle formulation of LDN-57444 by incorporation of the compound in polyoxazoline micellear nanoparticles (LDN-POx). LDN-POx nanoparticles were equal in effects as the native compound in vitro. Our results demonstrate that inhibition of UCH-L1 DUB activity with LDN or LDN-POx inhibits secretion of exosomes and reduces levels of the pro-metastatic factor in exosomal fractions. Both forms of UCH-L1 DUB inhibitor suppress motility of metastatic squamous carcinoma cells as well as nasopharyngeal cells expressing EBV pro-metastatic Latent membrane protein 1 (LMP1) in physiological assays. Moreover, treatment with LDN and LDN-POx resulted in reduced levels of pro-metastatic markers, a decrease of carcinoma cell adhesion, as well as inhibition of extra-cellular vesicle (ECV)-mediated transfer of viral invasive factor LMP1. We suggest that soluble inhibitors of UCH-L1 such as LDN-POx offer potential forms of treatment for invasive carcinomas including EBV-positive malignancies.

scholarly journals Hydroxy-Propil-β-Cyclodextrin Inclusion Complexes of two Biphenylnicotinamide Derivatives: Formulation and Anti-Proliferative Activity Evaluation in Pancreatic Cancer Cell Models

2020 ◽  
Vol 21 (18) ◽  
pp. 6545
Author(s):  
Rosa Maria Iacobazzi ◽  
Annalisa Cutrignelli ◽  
Angela Stefanachi ◽  
Letizia Porcelli ◽  
Angela Assunta Lopedota ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Inclusion Complexes ◽  
Water Solubility ◽  
Aqueous Solubility ◽  
Ductal Adenocarcinoma ◽  
New Therapeutic Approaches ◽  
M Phase ◽  
High Antitumor Activity ◽  
Poor Outcomes

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with poor outcomes largely due to its unique microenvironment, which is responsible for the low response to drugs and drug-resistance phenomena. This clinical need led us to explore new therapeutic approaches for systemic PDAC treatment by the utilization of two newly synthesized biphenylnicotinamide derivatives, PTA73 and PTA34, with remarkable antitumor activity in an in vitro PDAC model. Given their poor water solubility, inclusion complexes of PTA34 and PTA73 in Hydroxy-Propil-β-Cyclodextrin (HP-β-CD) were prepared in solution and at the solid state. Complexation studies demonstrated that HP-β-CD is able to form stable host–guest inclusion complexes with PTA34 and PTA73, characterized by a 1:1 apparent formation constant of 503.9 M−1 and 369.2 M−1, respectively (also demonstrated by the Job plot), and by an increase in aqueous solubility of about 150 times (from 1.95 µg/mL to 292.5 µg/mL) and 106 times (from 7.16 µg/mL to 762.5 µg/mL), in the presence of 45% w/v of HP-β-CD, respectively. In vitro studies confirmed the high antitumor activity of the complexed PTA34 and PTA73 towards PDAC cells, the strong G2/M phase arrest followed by induction of apoptosis, and thus their eligibility for PDAC therapy.

scholarly journals Cytotoxic Activity of Crude Extracts as well as of Pure Components fromJatrophaSpecies, Plants Used Extensively in African Traditional Medicine

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Olapeju O. Aiyelaagbe ◽  
Amao A. Hamid ◽  
Ernesto Fattorusso ◽  
Orazio Taglialatela-Scafati ◽  
Heinz C. Schröder ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Traditional Medicine ◽  
Neuronal Cell ◽  
Carcinoma Cells ◽  
Cervix Carcinoma ◽  
Highly Active ◽  
African Traditional Medicine ◽  
Growth Of Tumor ◽  
Mouse Lymphoma

Extracts fromJatropha curcas, a plant used in African traditional medicine for various diseases, were tested for cytotoxic activity. The root extracts strongly reduced cell growth of tumor cellsin vitro, a result consistent with the knowledge of the application of these plant extracts in traditional medicine, especially to cure/ameliorate cancer. A selection of pure diterpenoids existing in extracts fromJatrophaspecies and isolated fromJ. curcas, for example, curcusone C, curcusone D, multidione, 15-epi-4Z-jatrogrossidentadion, 4Z-jatrogrossidentadion, 4E-jatrogrossidentadion, 2-hydroxyisojatrogrossidion, and 2-epi-hydroxyisojatrogrossidion, were likewise tested, and they also showed strong cytotoxic activity. It turned out that these extracts are highly active against L5178y mouse lymphoma cells and HeLa human cervix carcinoma cells, while they cause none or only very low activity against neuronal cell, for example, PC12. These data underscore that extracts fromJ. curcasor pure secondary metabolites from the plant are promising candidates to be anticancer drug, combined with low neuroactive effects.

scholarly journals The common neoantigens in colorectal cancer are predicted and validated to be presented or immunogenic

2019 ◽  
Author(s):  
Zhaoduan Liang ◽  
Lili Qin ◽  
Lei Chen ◽  
Wenhui Li ◽  
Chao Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Regression ◽  
Individual Treatment ◽  
Cytotoxic Lymphocyte ◽  
Oncogenic Mutations ◽  
Incidence And Mortality ◽  
High Incidence ◽  
The Common ◽  
High Binding Affinity

ABSTRACTColorectal cancer (CRC) is a malignant cancer with high incidence and mortality in the world, as the result of the traditional treatments. Immunotherapy targeting neoantigens can induce durable tumor regression in cancer patients, but is almost limited to individual treatment, resulting from the unique neoantigens. Many shared oncogenic mutations are detected, but whether the common neoantigens can be identified in CRC is unknown. Using the somatic mutations data from 321 CRC patients combined with a filter standard and 7 predicted algorithms, we screened and obtained 25 HLA-A*11:01 restricted common neoantigens with high binding affinity (IC50<50 nM) and presentation score (>0.9). Except the positive epitope KRAS_G12V8-16, 11 out of 25 common neoantigens were proved to be naturally processed and presented on constructed K562 cell surface by mass spectroscopy (MS), and 11 out of 25 common neoantigens specifically induced in vitro pre-stimulated cytotoxic lymphocyte (CTL) to secrete IFN-γ. However, only 2 out of 25 common neoantigens were simultaneously presented and immunogenic. Moreover, using cell-sorting technology combined with single-cell RNA sequencing, the immune repertoire profiles of C1orf170_S418G413-421 and KRAS_G12V8-16-specific CTL were clarified. Therefore, common neoantigens with presentation and immunogenicity could be found in CRC, which would be developed as the universal targets for CRC immunotherapy.

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