Sustainable trehalose lipid production by Rhodotorula sp.: a promising bio-based alternative.

Global environmental concerns drive research toward the development of new eco-friendly compounds to replace pollutant chemicals. This study focuses on optimizing the production of trehalose lipids (TLs), which are glycolipid biosurfactants (BS) with various applications like antimicrobial or surface tension reduction. New microorganism sources, growth conditions, medium composition, purification conditions, and physicochemical properties of TLs are studied. Addressing a microscale approach, TLs production was successfully achieved using Rhodotorula sp. and Rhodococcus erythropolis to compare, with different media compositions including glucose-based and salt media supplemented with glycerol, glucose, n-hexadecane, n-dodecane. Liquid-liquid extraction using ethyl acetate and methanol was employed for compound extraction, followed by characterization using analytical methods such as Thin layer chromatography (TLC), High performance liquid chromatography (HPLC), and UHPLC. The produced TLs exhibited a minimum surface tension of 47 mN/m and a critical micellar concentration of 4.4 mg/mL. This study also identified Rhodotorula sp. as a new sustainable producer of TLs with improved productivity.

Screening the dermatological potential of plectranthus species components: antioxidant and inhibitory capacities over elastase, collagenase and tyrosinase.

A series of Plectranthus spp. plant extracts (aqueous, acetonic, methanolic and ethyl acetic) obtained from eight different species, and previously isolated compounds (ranging from polyphenols, diterpenes and triterpenes), were assayed for in vitro inhibition of the skin-related enzymes tyrosinase, collagenase and elastase, and for studying their antioxidant properties. The ethyl acetic extracts of P. grandidentatus and P. ecklonii registered the highest antioxidant activity, whereas acetonic, methanolic and ethyl acetic extracts of P. ecklonii, P. grandidentatus, P. madagascariensis and P. saccatus concerning the enzymatic inhibition assays revealed high anti-tyrosinase and anti-collagenase activities. From the isolated compounds tested, abietane diterpenes and triterpenes were highly active against tyrosinase and elastase activity. Overall, the experimental results showed the powerful antioxidant and inhibitory action on skin-related enzymes tyrosinase, collagenase and elastase of Plectranthus spp. extracts and/or isolated compounds, supporting their further research as bioactive metabolites against skin sagging and hyperpigmentation in cosmetic and pharmaceutical formulations.

Nanotechnological strategies for nerve growth factor delivery: Therapeutic implications in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with amyloid-ß peptide misfolding and aggregation. Neurotrophic factors, such as nerve growth factor (NGF), can prevent neuronal damage and rescue the cholinergic neurons that undergo cell death in AD, reverse deposition of extracellular amyloid plaques and improve cognitive deficits. However, NGF administration is hampered by the poor pharmacokinetic profile of the therapeutic protein and its inability to cross the blood-brain barrier, which requires specialised drug delivery systems (DDS) for efficient NGF delivery to the brain. This review covers the main therapeutic approaches that have been developed for NGF delivery targeting the brain, from polymeric implants to gene and cell-based therapies, focusing on the role of nanoparticulate systems for the sustained release of NGF in the brain as a neuroprotective and disease-modifying approach toward AD. Lipid- and polymer-based delivery systems, magnetic nanoparticles and quantum dots are specifically addressed as promising nanotechnological strategies to overcome the current limitations of NGF-based therapies.

Development of novel sophorolipids with improved cytotoxic activity toward MDA-MB-231 breast cancer cells.

Sophorolipids (SLs) are glycolipid biosurfactants, produced as a mixture of several compounds by some nonpathogenic yeast. In the current study, separation of individual SLs from mixtures with further evaluation of their surface properties and biologic activity on MDA-MB-321 breast cancer cell line were investigated. SLs were biosynthesized by Starmerella bombicola in a culture media supplemented with borage oil. A reverse-phase flash chromatography method with an automated system coupled with a prepacked cartridge was used to separate and purify the main SLs. Compositional analysis of SLs was performed by high-performance liquid chromatography with electrospray ionization mass spectrometry and tandem mass spectrometry. The following diacetylated lactonic SLs were isolated and purified: C18:0, C18:1, C18:2, and C18:3. The critical micelle concentration (CMC) and surface tension at CMC (γCMC ) of the purified SLs showed an increase with the number of double bonds. High cytotoxic effect against MDA-MB-231 cells was observed with C18:0 and C18:1 lactonic SLs. The cytotoxic effects of C18:3 lactonic SL on cancerous cells were for the first time studied. This cytotoxic effect was considerably higher than the promoted by acidic SLs; however, it induced a lower effect than the previously mentioned SLs, C18:0 and C18:1. To our knowledge, for the first time, C18:1 lactonic SL, in selected concentrations, proved to be able to inhibit MDA-MB-231 cell migration without compromising cell viability and to increase intracellular reactive oxygen species.

Triterpenes as Potential Drug Candidates for Rheumatoid Arthritis Treatment.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by joint inflammation, swelling and pain. Although RA mainly affects the joints, the disease can also have systemic implications. The presence of autoantibodies, such as anti-cyclic citrullinated peptide antibodies and rheumatoid factors, is a hallmark of the disease. RA is a significant cause of disability worldwide associated with advancing age, genetic predisposition, infectious agents, obesity and smoking, among other risk factors. Currently, RA treatment depends on anti-inflammatory and disease-modifying anti-rheumatic drugs intended to reduce joint inflammation and chronic pain, preventing or slowing down joint damage and disease progression. However, these drugs are associated with severe side effects upon long-term use, including immunosuppression and development of opportunistic infections. Natural products, namely triterpenes with anti-inflammatory properties, have shown relevant anti-arthritic activity in several animal models of RA without undesirable side effects. Therefore, this review covers the recent studies (2017-2022) on triterpenes as safe and promising drug candidates for the treatment of RA. These bioactive compounds were able to produce a reduction in several RA activity indices and immunological markers. Celastrol, betulinic acid, nimbolide and some ginsenosides stand out as the most relevant drug candidates for RA treatment.

Triterpenes Drug Delivery Systems, a Modern Approach for Arthritis Targeted Therapy.

Arthritis is a major cause of disability. Currently available anti-arthritic drugs, such as disease-modifying anti-rheumatic drugs (DMARDs), have serious side-effects associated with long-term use. Triterpenoids are natural products with known anti-inflammatory properties, and many have revealed efficiency against arthritis both in vitro and in vivo in several animal models, with negligible cytotoxicity. However, poor bioavailability due to low water solubility and extensive metabolism upon oral administration hinder the therapeutic use of anti-arthritic triterpenoids. Therefore, drug delivery systems (DDSs) able to improve the pharmacokinetic profile of triterpenoids and achieve sustained drug release are useful alternatives for targeted delivery in arthritis treatment. Several DDSs have been described in the literature for triterpenoid delivery, including microparticulate and nanoparticulate DDSs, such as polymeric micro and nanoparticles (NPs), polymeric micelles, liposomes, micro and nanoemulsions, and hydrogels. These systems have shown superior therapeutic effects in arthritis compared to the free drugs and are similar to currently available anti-arthritic drugs without significant side-effects. This review focuses on nanocarriers for triterpenoid delivery in arthritis therapy, including osteoarthritis (OA), rheumatoid arthritis (RA) and gout that appeared in the literature in the last ten years.

Exploring Functionalized Magnetic Hydrogel Polyvinyl Alcohol and Chitosan Electrospun Nanofibers.

Nanofibrous materials present interesting characteristics, such as higher area/mass ratio and reactivity. These properties have been exploited in different applications, such as drug-controlled release and site-specific targeting of biomolecules for several disease treatments, including cancer. The main goal of this study was to develop magnetized nanofiber systems of lysozyme (Lys) for biological applications. The system envisaged electrospun polyvinyl alcohol (PVA) and PVA/chitosan (CS) nanofibers, loaded with Lys, crosslinked with boronic acids [phenylboronic acid (PBA), including 2-acetylphenylboronic acid (aPBA), 2-formylphenylboronic (fPBA), or bortezomib (BTZ)] and functionalized with magnetic nanobeads (IONPs), which was successfully built and tested using a microscale approach. Evaluation of the morphology of nanofibers, obtained by electrospinning, was carried out using SEM. The biological activities of the Lys-loaded PVA/CS (90:10 and 70:30) nanofibers were evaluated using the Micrococcus lysodeikticus method. To evaluate the success of the encapsulation process, the ratio of adsorbed Lys on the nanofibers, Lys activity, and in vitro Lys release were determined in buffer solution at pH values mimicking the environment of cancer cells. The viability of Caco-2 cancer cells was evaluated after being in contact with electrospun PVA + Lys and PVA/CS + Lys nanofibers, with or without boronic acid functionalation, and all were magnetized with IONPs.

Analytical Rheology of Honey: A State-of-the-Art Review.

Honey has been used as a nutraceutical product since ancient times due to its nutritional and medicinal properties. Honey rheology influences its organoleptic properties and is relevant for processing and quality control. This review summarizes the rheological behaviour of honeys of different botanical source(s) and geographical locations that has been described in the literature, focusing on the relation between rheological parameters, honey composition (moisture, water activity, sugar content, presence of colloidal matter) and experimental conditions (temperature, time, stress, shear rate). Both liquid and crystallized honeys have been addressed. Firstly, the main mathematical models used to describe honey rheological behaviour are presented highlighting moisture and temperature effects. Then, rheological data from the literature regarding distinct honey types from different countries is analysed and results are compared. Although most honeys are Newtonian fluids, interesting shear-thinning and thixotropic as well as anti-thixotropic behaviour have been described for some types of honey. Rheological parameters have also been successfully applied to identify honey adulteration and to discriminate between different honey types. Several chemometric techniques have also been employed to obtain the complex relationships between honey physicochemical and rheological properties, including partial least squares (PLS), principal component analysis (PCA) and artificial neural networks (ANN).

Dehydroabietic Acid Microencapsulation Potential as Biofilm-Mediated Infections Treatment.

The antimicrobial activity of dehydroabietic acid (DHA) for its use as an antibiofilm agent was tested in this work. DHA was assayed against a collection of Gram-positive, Gram-negative sensitive and resistant bacteria and yeasts through the minimum inhibitory concentration (MIC), MIC with Bioburden challenge, minimum bactericidal concentration (MBC), minimum biofilm inhibitory concentration (MBIC), MBIC with Bioburden challenge and growth curve studies. Toxicological studies (Artemia salina, sulforhodamine B (SRB) assay) were done to assess if the compound had antimicrobial and not cytotoxic properties. Furthermore, microencapsulation and stability studies were carried out to evaluate the chemical behavior and stability of DHA. On MIC results, Gram-positive bacteria Staphylococcus aureus ATCC 1228 and Mycobacterium smegmatis ATCC 607 presented a high efficiency (7.81 µg/mL), while on Gram-negative bacteria the highest MIC value of 125 µg/mL was obtained by all Klebsiella pneumoniae strains and Escherichia coli isolate strain HSM 303. Bioburden challenge showed that MIC, MBIC and percentage biofilm inhibition (BI) values suffered alterations, therefore, having higher concentrations. MBIC values demonstrated that DHA has a higher efficiency against S. aureus ATCC 43866 with a percentage of BI of 75.13 ± 0.82% at 0.49 µg/mL. Growth curve kinetic profiles of DHA against S. aureus ATCC 25923 were observed to be bacteriostatic. DHA-alginate beads had a average size of 2.37 ± 0.20 and 2.31 ± 0.17 × 103 µm2 with an encapsulation efficiency (EE%) around 99.49 ± 0.05%, a protection percentage (PP%) of 60.00 ± 0.05% in the gastric environment and a protection efficiency (PE%) around 88.12 ± 0.05% against UV light. In toxicological studies DHA has shown IC50 of 19.59 ± 7.40 µg/mL and a LC50 of 21.71 ± 2.18%. The obtained results indicate that DHA is a promising antimicrobial candidate against a wide range of bacteria and biofilm formation that must be further explored.

Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy.

Amphotericin B (AmB), a broad-spectrum polyene antibiotic in the clinic for more than fifty years, remains the gold standard in the treatment of life-threatening invasive fungal infections and visceral leishmaniasis. Due to its poor water solubility and membrane permeability, AmB is conventionally formulated with deoxycholate as a micellar suspension for intravenous administration, but severe infusion-related side effects and nephrotoxicity hamper its therapeutic potential. Lipid-based formulations, such as liposomal AmB, have been developed which significantly reduce the toxic side effects of the drug. However, their high cost and the need for parenteral administration limit their widespread use. Therefore, delivery systems that can retain or even enhance antimicrobial efficacy while simultaneously reducing AmB adverse events are an active area of research. Among those, lipid systems have been extensively investigated due to the high affinity of AmB for binding lipids. The development of a safe and cost-effective oral formulation able to improve drug accessibility would be a major breakthrough, and several lipid systems for the oral delivery of AmB are currently under development. This review summarizes recent advances in lipid-based systems for targeted delivery of AmB focusing on non-parenteral nanoparticulate formulations mainly investigated over the last five years and highlighting those that are currently in clinical trials.

A scope at antifouling strategies to prevent catheter-associated infections.

The use of invasive medical devices is becoming more common nowadays, with catheters representing one of the most used medical devices. However, there is a risk of infection associated with the use of these devices, since they are made of materials that are prone to bacterial adhesion with biofilm formation, often requiring catheter removal as the only therapeutic option. Catheter-related urinary tract infections (CAUTIs) and central line-associated bloodstream infections (CLABSIs) are among the most common causes of healthcare-associated infections (HAIs) worldwide while endotracheal intubation is responsible for ventilator-associated pneumonia (VAP). Therefore, to avoid the use of biocides due to the potential risk of bacterial resistance development, antifouling strategies aiming at the prevention of bacterial adherence and colonization of catheter surfaces represent important alternative measures. This review is focused on the main strategies that are able to modify the physical or chemical properties of biomaterials, leading to the creation of antiadhesive surfaces. The most promising approaches include coating the surfaces with hydrophilic polymers, such as poly(ethylene glycol) (PEG), poly(acrylamide) and poly(acrylates), betaine-based zwitterionic polymers and amphiphilic polymers or the use of bulk-modified poly(urethanes). Natural polysaccharides and its modifications with heparin, have also been used to improve hemocompatibility. Recently developed bioinspired techniques yielding very promising results in the prevention of bacterial adhesion and colonization of surfaces include slippery liquid-infused porous surfaces (SLIPS) based on the superhydrophilic rim of the pitcher plant and the Sharklet topography inspired by the shark skin, which are potential candidates as surface-modifying approaches for biomedical devices. Concerning the potential application of most of these strategies in catheters, more in vivo studies and clinical trials are needed to assure their efficacy and safety for possible future use.

A Glance at Antimicrobial Strategies to Prevent Catheter-Associated Medical Infections.

Urinary and intravascular catheters are two of the most used invasive medical devices; however, microbial colonization of catheter surfaces is responsible for most healthcare-associated infections (HAIs). Several antimicrobial-coated catheters are available, but recurrent antibiotic therapy can decrease their potential activity against resistant bacterial strains. The aim of this Review is to question the actual effectiveness of currently used (coated) catheters and describe the progress and promise of alternative antimicrobial coatings. Different strategies have been reviewed with the common goal of preventing biofilm formation on catheters, including release-based approaches using antibiotics, antiseptics, nitric oxide, 5-fluorouracil, and silver as well as contact-killing approaches employing quaternary ammonium compounds, chitosan, antimicrobial peptides, and enzymes. All of these strategies have given proof of antimicrobial efficacy by modifying the physiology of pathogens or disrupting their structural integrity. The aim for synergistic approaches using multitarget processes and the combination of both antifouling and bactericidal properties holds potential for the near future. Despite intensive research in biofilm preventive strategies, laboratorial studies still present some limitations since experimental conditions usually are not the same and also differ from biological conditions encountered when the catheter is inserted in the human body. Consequently, in most cases, the efficacy data obtained from in vitro studies is not properly reflected in the clinical setting. Thus, further well-designed clinical trials and additional cytotoxicity studies are needed to prove the efficacy and safety of the developed antimicrobial strategies in the prevention of biofilm formation at catheter surfaces.

New urea-based surfactants derived from alpha,omega-amino acids.

New anionic urea-based surfactants derived from alpha,omega-amino acids and in particular from beta-alanine were synthesized and their solution properties characterized by electrical conductivity, equilibrium surface tension, and steady-state fluorescence spectroscopy techniques. Double-chain surfactants and the single-chain surfactant containing a sulfate head group exhibited the lowest critical micelle concentration (cmc) values and superior efficiency in lowering surface tension. All surfactants promoted adsorption relative to micellization, and micellar parameters were sensitive to the hydrophobicity of the amino acid residue. The polarity of the interfacial region, measured with the solvatochromic probe E(T)(30) (Reichardt's betaine dye), was similar to sodium dodecyl sulfate (SDS) micelles.

Gemini surfactant-protein interactions: effect of pH, temperature, and surfactant stereochemistry.

The interactions between bovine serum albumin (BSA) and gemini surfactants derived from cystine have been investigated and were compared with the conventional single-chain surfactant derived from cysteine. The influence of the stereochemistry of the gemini surfactant on its behavior toward BSA was also investigated, as well as the effects of pH and temperature. Electrical conductivity and surface tension measurements were used to obtain important system parameters such as critical aggregation concentration (cac), polymer saturation point (psp), degree of ionization (alpha), and the amount of surfactant binding to protein (M). Stereochemistry was found to influence the surface properties of the surfactants studied and their interaction with BSA but not their micellar properties in solution.

Therapeutic Strategies Targeting Amyloid-ß in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder linked to protein misfolding and aggregation. AD is pathologically characterized by senile plaques formed by extracellular Amyloid-ß (Aß) peptide and Intracellular Neurofibrillary Tangles (NFT) formed by hyperphosphorylated tau protein. Extensive synaptic loss and neuronal degeneration are responsible for memory impairment, cognitive decline and behavioral dysfunctions typical of AD. Amyloidosis has been implicated in the depression of acetylcholine synthesis and release, overactivation of N-methyl-D-aspartate (NMDA) receptors and increased intracellular calcium levels that result in excitotoxic neuronal degeneration. Current drugs used in AD treatment are either cholinesterase inhibitors or NMDA receptor antagonists; however, they provide only symptomatic relief and do not alter the progression of the disease. Aß is the product of Amyloid Precursor Protein (APP) processing after successive cleavage by ß- and γ-secretases while APP proteolysis by α-secretase results in non-amyloidogenic products. According to the amyloid cascade hypothesis, Aß dyshomeostasis results in the accumulation and aggregation of Aß into soluble oligomers and insoluble fibrils. The former are synaptotoxic and can induce tau hyperphosphorylation while the latter deposit in senile plaques and elicit proinflammatory responses, contributing to oxidative stress, neuronal degeneration and neuroinflammation. Aß-protein-targeted therapeutic strategies are thus a promising disease-modifying approach for the treatment and prevention of AD. This review summarizes recent findings on Aß-protein targeted AD drugs, including ß-secretase inhibitors, γ-secretase inhibitors and modulators, α-secretase activators, direct inhibitors of Aß aggregation and immunotherapy targeting Aß, focusing mainly on those currently under clinical trials.

Cytotoxic Activity of Royleanone Diterpenes from Plectranthus madagascariensis Benth.

Cytotoxicity screenings have identified Plectranthus plants as potential sources of antitumor lead compounds. In this work, several extracts from Plectranthus madagascariensis were prepared using different solvents (acetone, methanol, and supercritical CO2) and extraction techniques (maceration, ultrasound-assisted, and supercritical fluid extraction), and their chemical composition was detailed using high-performance liquid chromatography with a diode array detector. The cytotoxic activity of the major compounds identified, namely, rosmarinic acid (1) and abietane diterpenes 7α,6ß-dihydroxyroyleanone (2), 7α-formyloxy-6ß-hydroxyroyleanone (3), 7α-acetoxy-6ß-hydroxyroyleanone (4), and coleon U (5), was evaluated in a battery of human cancer cell lines, including breast (MDA-MB-231, MCF-7), colon (HCT116), and lung (NCI-H460, NCI-H460/R) cancer, and also in healthy lung (MCR-5) cells. Royleanone (3) was isolated for the first time from P. madagascariensis, and its full spectroscopic characterization (proton and carbon nuclear magnetic resonance) was accomplished. A high selectivity for lung cancer cells was observed for royleanones (2, 4) with selectivity indexes of 4.3 and 3.2, respectively. The observed results combined with literature data allowed the establishment of important structure-activity relationships for substituted royleanone abietanes, such as the requirement for an electron-donating group at positions 6 and/or 7 in the abietane skeleton, and an improved cytotoxic effect for substituents with log P values between 2 and 5.

Comparison Study of Different Extracts of Plectranthus madagascariensis, P. neochilus and the Rare P. porcatus (Lamiaceae): Chemical Characterization, Antioxidant, Antimicrobial and Cytotoxic Activities.

Medicinal plants of the Plectranthus genus (Lamiaceae) are known for their ethnopharmacological relevance, mainly against infectious, dermatologic and gastrointestinal pathologies. Three Plectranthus species originated from South Africa, namely P. madagascariensis, P. neochilus and the rare P. porcatus were hereby screened for their antimicrobial and cytotoxic activities related with their known and/or potential ethnomedicinal uses. Twenty-six extracts were prepared by the combination of extraction methods (infusion, decoction, microwave-assisted, ultrasound-assisted, maceration and supercritical fluid extraction) with different polarity solvents (water, methanol, acetone and supercritical CO2). The comparison study of these extracts was elucidated through the corresponding chemical characterization and cytotoxic activity data. Therefore, the acetone extract from P. madagascariensis prepared by ultrasound extraction method revealed potent antibacterial activity against Gram-positive bacteria (1.95 < minimum inhibitory concentration (MIC) < 7.81 µg/mL), including a methicillin-resistant Staphylococcus aureus (MRSA) strain. Additionally, acetone extracts from both P. madagascariensis and P. neochilus exhibited relevant antibacterial activity against Gram-negative Klebsiella pneumonia (0.48 < MIC < 3.91 µg/mL), validating the traditional uses of such plants as anti-infectious agents. All methanolic extracts showed potent antioxidant effects at 100 µg/mL measured as their radical scavenging activity (60.8-89.0%) in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. The P. madagascariensis extract obtained by maceration in acetone showed moderate cytotoxic effects in the MDA-MB-231 cell line (triple negative human breast carcinoma). The extract concentration that caused a 50% inhibition in cell viability (IC50) was 64.52 µg/mL. All extracts in this comparative study were profiled by high-performance liquid chromatography-HPLC with a diode-array detector-DAD (HPLC-DAD) and the main known bioactive components were identified in each extract, which included polyphenols (caffeic 1, chlorogenic 2 and rosmarinic 3 acids), abietane diterpenes (7α-acetoxy-6ß-hydroxyroyleanone 4 and coleon U 5) and flavone glycosides (rutin 6 and naringin 7).

Cytotoxicity and Chemotherapeutic Potential of Natural Rosin Abietane Diterpenoids and their Synthetic Derivatives.

Cancer is a major cause of morbidity and mortality worldwide. Chemotherapeutic agents currently used in cancer treatment are associated with severe side effects and development of resistance. Thus, there is a pressing need for novel and more potent anticancer drugs with high selectivity for tumor cells and reduced toxicity to normal tissue. Natural products remain an important source of bioactive compounds and drug prototypes that can lead to new and more effective antitumor agents. Coniferous plants are rich in abietane diterpenoids with a wide range of biological activities that provide useful templates for synthetic modification. Abietic acid and dehydroabietic acid (DHA), the major diterpenic resin acids from Pinus rosin, and dehydroabietylamine found in commercial disproportionated rosin amine, display antibacterial and antitumor properties. These compounds and their synthetic derivatives have been reported as promising anticancer agents with potent growth inhibitory activity against several types of human cancer cell lines, including breast, ovarian, prostate, colon, liver, lung and cervical carcinoma cells. Their mechanisms of action are diverse and include DNA binding, induction of apoptosis or oncosis, tubulin polymerization inhibition and disruption of intracellular cholesterol transport. This review covers the main aspects of natural rosin abietane diterpenoids (abietic acid, DHA and DHAA) and synthetic derivatives concerning their anti-proliferative, cytotoxic and antitumor activities, mechanisms of action and structure- activity relationships relevant for the development of novel anticancer agents for cancer chemotherapy.

Anticancer Hybrid Combinations: Mechanisms of Action, Implications and Future Perspectives.

The exponential growth of cancer cases worldwide together with recent advances concerning the pathophysiological mechanisms of the disease at the molecular level led to a paradigm shift in chemotherapy, from monotherapy to targeted drug combination regimens. However, adverse effects and the emergence of multidrug resistance (MDR) limit the effectiveness of these therapies. In this context, hybrid combinations mixing anticancer drugs and bioactive phytochemical components from medicinal plants, or even plant extracts, that can act synergistically on multiple targets and signaling pathways represent a promising approach with the potential to expand the current therapeutic arsenal. This review aims to provide a synopsis on anticancer hybrid combinations based on their multi-target mechanisms and synergistic effects from an extensive literature search focusing mainly on publications from the last ten years. In most of these combinations, the phytochemical component was shown to enhance the anticancer activity of the chemotherapeutic agent and to sensitize chemoresistant tumors in several types of cancer. Hybrid combinations, due to synergistic interactions, are also associated with less severe adverse events since lower doses can be used to achieve the same therapeutic effect. Further preclinical and clinical studies are needed, as well as the development of an adequate regulatory framework, before hybrid combination therapy can be translated into clinical practice.

Cytotoxic Stilbenes and Derivatives as Promising Antimitotic Leads for Cancer Therapy.

The growing incidence of cancer, the toxic side-effects associated with conventional chemotherapeutic agents and the development of multidrug resistance (MDR) drive the search for novel and more effective drugs with multi-target activity and selectivity towards cancer cells. Stilbenes are a group of naturally occurring phenolic compounds of plant origin derived from the phenylpropanoid pathway that may exist as cis- or trans-isomers. Although the trans-isomer is the more common and stable configuration, resveratrol being a representative compound, cis-stilbenes are potent cytotoxic agents that bind to and inhibit tubulin polymerization, destabilizing microtubules. This review summarizes the chemistry and biological evaluation of cytotoxic stilbenes and their synthetic derivatives as promising antimitotic leads for cancer therapy, focusing on the most potent compounds, the combretastatins. Combretastatins isolated from the South African bushwillow Combretum caffrum are among the most potent antimitotic and vascular disrupting agents (VDAs) of natural origin. Preclinical studies have demonstrated their potent antitumor effects in a wide variety of tumors, both in vitro and in vivo, being currently under evaluation in phase 2 and phase 3 clinical trials for several types of solid tumors. Topics covered herein include synthetic medicinal chemistry, modes of action, structure-activity relationships (SAR), preclinical and clinical studies as VDAs in cancer therapy, either as single agents or in combination with cytotoxic anticancer drugs, antiangiogenic agents, or radiation therapy, and development of appropriate formulations based on nanocarriers (e.g., liposomes, nanoemulsions, polymeric, lipid and ceramic nanoparticles, carbon nanotubes) for improved bioavailability and targeted delivery of combretastatins to the tumor vasculature.