A novel hybrid drug between two potent anti-tubulin agents as a potential prolonged anticancer approach

Marchetti, Paolo; Pavan, Barbara; Daniele, Simona; Baruchello, Riccardo; Rondanin, Riccardo; Mischiati, Carlo; Feriotto, Giordana; Ferraro, Luca; Hsu, Lih Ching; Lee, Ray M.; Dalpiaz, Alessandro

doi:10.1016/j.ejps.2016.05.032

Cited by 8 publications

(5 citation statements)

References 39 publications

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“…As a consequence, the geraniol rate from the apical to basolateral compartments was roughly sixfold higher than its permeation in the opposite direction ( P < 0.001). On the other hand, celiprolol, a drug known to be a substrate of the P-gp efflux transporter ( Karlsson et al, 1993 ) expressed by NCM460 monolayers ( Marchetti et al, 2016 ), showed an opposite behavior to that of geraniol, the celiprolol rate from basolateral to apical compartments being significantly higher than its rate in the opposite direction ( Marchetti et al, 2016 ). The P E values of geraniol, indomethacin and celiprolol were all obtained in our laboratory under the same experimental conditions using the same cell line and analytical instruments.…”

Section: Discussionmentioning

confidence: 99%

Geraniol Pharmacokinetics, Bioavailability and Its Multiple Effects on the Liver Antioxidant and Xenobiotic-Metabolizing Enzymes

et al. 2018

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Geraniol is a natural monoterpene showing anti-inflammatory, antioxidant, neuroprotective and anticancer effects. No pharmacokinetic and bioavailability data on geraniol are currently available. We therefore performed a systematic study to identify the permeation properties of geraniol across intestinal cells, and its pharmacokinetics and bioavailability after intravenous and oral administration to rats. In addition, we systematically investigated the potential hepatotoxic effects of high doses of geraniol on hepatic phase I, phase II and antioxidant enzymatic activities and undertook a hematochemical analysis on mice. Permeation studies performed via HPLC evidenced geraniol permeability coefficients across an in vitro model of the human intestinal wall for apical to basolateral and basolateral to apical transport of 13.10 ± 2.3 × 10-3 and 2.1 ± 0.1⋅× 10-3 cm/min, respectively. After intravenous administration of geraniol to rats (50 mg/kg), its concentration in whole blood (detected via HPLC) decreased following an apparent pseudo-first order kinetics with a half-life of 12.5 ± 1.5 min. The absolute bioavailability values of oral formulations (50 mg/kg) of emulsified geraniol or fiber-adsorbed geraniol were 92 and 16%, respectively. Following emulsified oral administration, geraniol amounts in the cerebrospinal fluid of rats ranged between 0.72 ± 0.08 μg/mL and 2.6 ± 0.2 μg/mL within 60 min. Mice treated with 120 mg/kg of geraniol for 4 weeks showed increased anti-oxidative defenses with no signs of liver toxicity. CYP450 enzyme activities appeared only slightly affected by the high dosage of geraniol.

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Section: Discussionmentioning

confidence: 99%

Geraniol Pharmacokinetics, Bioavailability and Its Multiple Effects on the Liver Antioxidant and Xenobiotic-Metabolizing Enzymes

et al. 2018

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“…The compound showed a potent antimitotic effect related to the inhibition of tubulin polymerization by binding to the Vinca alkaloid binding site [ 113 ]. Marchetti et al [ 114 ] have developed a hybrid drug by conjugating two tubulin inhibitors, one of which was hemiasterlin. This derivative possessed stronger and more potent anti-tubulin activity against human Caucasian ovary adenocarcinoma SKOV3 cells [ 114 ].…”

Section: Mnp-based Drugs That Are Approved or In Ongoing Clinical mentioning

confidence: 99%

“…Marchetti et al [ 114 ] have developed a hybrid drug by conjugating two tubulin inhibitors, one of which was hemiasterlin. This derivative possessed stronger and more potent anti-tubulin activity against human Caucasian ovary adenocarcinoma SKOV3 cells [ 114 ]. Taltobulin (HTI286), another hemiasterlin derivative, is also in phase I clinical trials [ 84 ].…”

Section: Mnp-based Drugs That Are Approved or In Ongoing Clinical mentioning

confidence: 99%

An Updated Review on Marine Anticancer Compounds: The Use of Virtual Screening for the Discovery of Small-Molecule Cancer Drugs

et al. 2017

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Marine secondary metabolites are a promising source of unexploited drugs that have a wide structural diversity and have shown a variety of biological activities. These compounds are produced in response to the harsh and competitive conditions that occur in the marine environment. Invertebrates are considered to be among the groups with the richest biodiversity. To date, a significant number of marine natural products (MNPs) have been established as antineoplastic drugs. This review gives an overview of MNPs, both in research or clinical stages, from diverse organisms that were reported as being active or potentially active in cancer treatment in the past seventeen years (from January 2000 until April 2017) and describes their putative mechanisms of action. The structural diversity of MNPs is also highlighted and compared with the small-molecule anticancer drugs in clinical use. In addition, this review examines the use of virtual screening for MNP-based drug discovery and reveals that classical approaches for the selection of drug candidates based on ADMET (absorption, distribution, metabolism, excretion, and toxicity) filtering may miss potential anticancer lead compounds. Finally, we introduce a novel and publically accessible chemical library of MNPs for virtual screening purposes.

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“…This behavior appears in good agreement with the well-known carboxylesterase activity in rodent plasma [ 37 ]. Accordingly, the hydrolysis of several ester prodrugs was previously identified in rat blood, together with the related release of antiviral, antitumor or antiparkinsonian agents [ 29 , 38 , 39 ].…”

Section: Resultsmentioning

confidence: 99%

Effects of Microencapsulated Ferulic Acid or Its Prodrug Methyl Ferulate on Neuroinflammation Induced by Muramyl Dipeptide

Botti

Bianchi

Pavan

et al. 2022

IJERPH

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Ferulic acid (Fer) is known for its antioxidant and anti-inflammatory activities, which are possibly useful against neurodegenerative diseases. Despite the ability of Fer to permeate the brain, its fast elimination from the body does not allow its therapeutic use to be optimized. The present study proposes the preparation and characterization of tristearin- or stearic acid-based solid lipid microparticles (SLMs) as sustained delivery and targeting systems for Fer. The microparticles were produced by conventional hot emulsion techniques. The synthesis of the methyl ester of Fer (Fer-Me) allowed its encapsulation in the SLMs to increase. Fer-Me was hydrolyzed to Fer in rat whole blood and liver homogenate, evidencing its prodrug behavior. Furthermore, Fer-Me displayed antioxidant and anti-inflammatory properties. The amount of encapsulated Fer-Me was 0.719 ± 0.005% or 1.507 ± 0.014% in tristearin or stearic acid SLMs, respectively. The tristearin SLMs were able to control the prodrug release, while the stearic acid SLMs induced a significant increase of its dissolution rate in water. Jointly, the present results suggest that the tristearin SLMs loaded with Fer-Me could be a potential formulation against peripheral neuropathic pain; conversely, the stearic acid SLMs could be useful for Fer-Me uptake in the brain after nasal administration of the formulation.

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A novel hybrid drug between two potent anti-tubulin agents as a potential prolonged anticancer approach

Cited by 8 publications

References 39 publications

Geraniol Pharmacokinetics, Bioavailability and Its Multiple Effects on the Liver Antioxidant and Xenobiotic-Metabolizing Enzymes

Geraniol Pharmacokinetics, Bioavailability and Its Multiple Effects on the Liver Antioxidant and Xenobiotic-Metabolizing Enzymes

An Updated Review on Marine Anticancer Compounds: The Use of Virtual Screening for the Discovery of Small-Molecule Cancer Drugs

Effects of Microencapsulated Ferulic Acid or Its Prodrug Methyl Ferulate on Neuroinflammation Induced by Muramyl Dipeptide

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