Chemistry and chemical biology of taxane anticancer agents

Taxol (paclitaxel) and Taxotere (docetaxel) are currently considered to be among the most important anticancer drugs in cancer chemotherapy. The anticancer activity of these drugs is ascribed to their unique mechanism of action, i.e., causing mitotic arrest in cancer cells, leading to apoptosis through inhibition of the depolymerization of microtubules. Although both paclitaxel and docetaxel possess potent antitumor activity, treatment with these drugs often results in a number of undesirable side effects, as well as multidrug resistance (MDR). Therefore, it has become essential to develop new anticancer agents with superior pharmacological properties, improved activity against various classes of tumors, and fewer side effects. This paper describes an account of our research on the chemistry of paclitaxel and taxoid anticancer agents at the biomedical interface, including: 1. The structure-activity relationship (SAR) study of taxoids leading to the development of the "second-generation" taxoids, which possess exceptional activity against drug-resistant cancer cells expressing the MDR phenotype. 2. Development of fluorinated taxoids to study the bioactive conformation of paclitaxel and photoaffinity labeling taxoids for mapping of the drug-binding domain on both microtubules and P-glycoprotein. 3. The synthesis of novel macrocyclic taxoids for the investigation into the common pharmacophore for microtubule stabilizing anticancer agents.     

Dual Electrode Liquid Chromatography-Electrochemical Detection (LCEC) for Platinum-Derived Cancer Chemotherapy Agents

Abstract

Trace methods of analysis and speciation have now been developed for a number of platinum derived anti-cancer chemotherapeutic agents, drugs such as: cis-dichloro diammine platinum (CDDP), cis-diammine-1,1-cyclobutane dicarboxylate platinum (CBDCA), and cis-dichloro-trans-dihydroxy diisopropylamine platinum (CHIP). It is possible to utilize parallel dual electrode operations for all three of these Pt derivatives, with overall improved analyte specificity and identification. At the same time, these approaches provide calibration plots of detector sensitivity as a function of the particular working electrode potentials in use via dual electrode LCEC. These response ratios as a function of the applied potentials then become quite unique for individual Pt compounds. By suitably selecting the operating electrode potentials in parallel operation, it is possible to alter the detectability of individual Pt analytes and to drastically vary the resultant LCEC chromatograms. The overall analyte selectivity possible via dual electrode LCEC surpasses that thus far possible via LC-polarographic reduction or single electrode LCEC operations. Glassy carbon as well as gold/mercury electrodes can readily be used for some of these Pt derivatives. These overall trace methods of analysis and speciation for the Pt anti-cancer agents have also been applied to plasma samples spiked with known levels of each drug. It is also possible to utilize these single or dual electrode approaches for the analysis of each of these Pt derivatives in cancer patients undergoing chemotherapy treatment.     

Metal based drugs: from serendipity to design

The platinum anticancer drug cisplatin has made a major contribution to the treatment of testicular and ovarian cancer. This chance discovery has been the stimulus for research into other metal-based drugs. Inorganic chemistry offers many opportunities for medicinal chemistry, and the discovery of metal-based drugs has moved on from chance discovery to rational drug design. There are however, many challenges associated with the drug discovery and development process. The aim of this review is to provide case histories exemplifying the role of rational drug design in modern inorganic medicinal chemistry in the context of these challenges. The evolution of platinum drugs from cisplatin to third generation drugs is described. The molecular target for the platinum agents is DNA. Alternative molecular targets such as thiol-containing proteins and redox processes are proposed. The example of a simple, safe, efficacious metal-based drug, Fosrenol, is reviewed.     

Jasmonate Compounds and Their Derivatives in the Regulation of the Neoplastic Processes

Cancer is a serious problem in modern medicine, mainly due to the insufficient effectiveness of currently available therapies. There is a particular interest in compounds of natural origin, which can be used in the prophylaxis, as well as in the treatment and support of cancer treatment. One such compound is jasmonic acid (3-oxo-2-(pent-2’-enyl)cyclopentane acetic acid; isolated active form: trans-(-)-(3R,7R)- and cis-(+)-(3R,7S)-jasmonic acid) and its derivatives, which, due to their wide range of biological activities, are also proposed as potential therapeutic agents. Therefore, a review of literature data on the biological activity of jasmonates was prepared, with particular emphasis on the mechanisms of jasmonate action in neoplastic diseases. The anti-tumor activity of jasmonate compounds is based on altered cellular ATP levels; induction of re-differentiation through the action of Mitogen Activated Protein Kinases (MAPKs); the induction of the apoptosis by reactive oxygen species. Jasmonates can be used in anti-cancer therapy in combination with other known drugs, such as cisplatin, paclitaxel or doxorubicin, showing a synergistic effect. The structure–activity relationship of novel jasmonate derivatives with anti-tumor, anti-inflammatory and anti-aging effects is also shown.     

Internalization of Ineffective Platinum Complex in Nanocapsules Renders It Cytotoxic

Anticancer therapy by platinum complexes, based on nanocarrier‐based delivery, may offer a new approach to improve the efficacy and tolerability of the platinum family of anticancer drugs. The original rules for the design of new anticancer platinum drugs were affected by the fact that, although cisplatin (cis‐[PtCl₂(NH₃)₂) was an anticancer drug, its isomer transplatin was not cytotoxic. For the first time, it is demonstrated that simple encapsulation of an inactive platinum compound in phospholipid bilayers transforms it into an efficient cytotoxic agent. Notably, the encapsulation of transplatin makes it possible to overcome the resistance mechanisms operating in cancer cells treated with cisplatin and prevents inactivation of transplatin in the extracellular environment. It is also shown that transplatin delivered to the cells in nanocapsules, in contrast to free (nonencapsulated) complex, forms cytotoxic cross‐links on DNA.     

LHRH/TAT dual peptides-conjugated polymeric vesicles for PTT enhanced chemotherapy to overcome hepatocellular carcinoma

Combination therapy such as photothermal therapy (PTT) enhanced chemotherapy is regarded as a promising strategy for cancer treatment. Herein, we developed redox-responsive polymeric vesicles based on the amphiphilic triblock copolymer PCL-ss-PEG-ss-PCL. To avoid the limited therapeutic effect of chemotherapeutic drugs caused by systemic exposures and drug resistance, the redox-sensitive polymeric vesicles were cargoed with two chemotherapeutics: doxorubicin (DOX) and paclitaxel (PTX). Besides, indocyanine green (ICG) was encapsulated, and cell-penetrating peptides and LHRH targeting molecule were modified on the surface of polymeric vesicles. The results indicated that the polymeric vesicles can load different kinds of drugs with high drug loading content, trigger drug release in responsive to the reductive environment, realize high cellular uptake via dual peptides and laser irradiation, and achieve higher cytotoxicity via chemo-photothermal combination therapy. Hence, the redox-responsive LHRH/TAT dual peptides-conjugated PTX/DOX/ICG co-loaded polymeric micelles exhibited great potential in tumor-targeting and chemo-photothermal therapy.     

Biocompatible APTES–PEG Modified Magnetite Nanoparticles: Effective Carriers of Antineoplastic Agents to Ovarian Cancer

Magnetite nanoparticles are particularly attractive for drug delivery applications because of their size-dependent superparamagnetism, low toxicity, and biocompatibility with cells and tissues. Surface modification of iron oxide nanoparticles with biocompatible polymers is potentially beneficial to prepare biodegradable nanocomposite-based drug delivery agents for in vivo and in vitro applications. In the present study, the bare (10 nm) and polyethylene glycol (PEG)–(3-aminopropyl)triethoxysilane (APTES) (PA) modified (17 nm) superparamagnetic iron oxide nanoparticles (SPIO NPs) were synthesized by coprecipitation method. The anticancer drugs, doxorubicin (DOX) and paclitaxel (PTX), were separately encapsulated into the synthesized polymeric nanocomposites for localized targeting of human ovarian cancer in vitro. Surface morphology analysis by scanning electron microscopy showed a slight increase in particle size (27?±?0.7 and 30?±?0.45 nm) with drug loading capacities of 70 and 61.5 % and release capabilities of 90 and 93 % for the DOX- and PTX-AP-SPIO NPs, respectively (p?<?0.001). Ten milligrams/milliliter DOX- and PTX-loaded AP-SPIO NPs caused a significant amount of cytotoxicity and downregulation of antiapoptotic proteins, as compared with same amounts of free drugs (p?<?0.001). In vivo antiproliferative effect of present formulation on immunodeficient female Balb/c mice showed ovarian tumor shrinkage from 2,920 to 143 mm³ after 40 days. The present formulation of APTES–PEG-SPIO-based nanocomposite system of targeted drug delivery proved to be effective enough in order to treat deadly solid tumor of ovarian cancer in vitro and in vivo.     

A programmable microfluidic cell array for combinatorial drug screening

We describe the development of a fully automatic and programmable microfluidic cell culture array that integrates on-chip generation of drug concentrations and pair-wise combinations with parallel culture of cells for drug candidate screening applications. The device has 64 individually addressable cell culture chambers in which cells can be cultured and exposed either sequentially or simultaneously to 64 pair-wise concentration combinations of two drugs. For sequential exposure, a simple microfluidic diffusive mixer is used to generate different concentrations of drugs from two inputs. For generation of 64 pair-wise combinations from two drug inputs, a novel time dependent variable concentration scheme is used in conjunction with the simple diffusive mixer to generate the desired combinations without the need for complex multi-layer structures or continuous medium perfusion. The generation of drug combinations and exposure to specific cell culture chambers are controlled using a LabVIEW interface capable of automatically running a multi-day drug screening experiment. Our cell array does not require continuous perfusion for keeping cells exposed to concentration gradients, minimizing the amount of drug used per experiment, and cells cultured in the chamber are not exposed to significant shear stress continuously. The utility of this platform is demonstrated for inducing loss of viability of PC3 prostate cancer cells using combinations of either doxorubicin or mitoxantrone with TRAIL (TNF-alpha Related Apoptosis Inducing Ligand) either in a sequential or simultaneous format. Our results demonstrate that the device can capture the synergy between different sensitizer drugs and TRAIL and demonstrate the potential of the microfluidic cell array for screening and optimizing combinatorial drug treatments for cancer therapy.     

Co-delivery of doxorubicin and paclitaxel with linear-dendritic block copolymer for enhanced anti-cancer efficacy

A series of well-defined amphiphilic linear-dendritic block copolymers (telodendrimers, MPEG-b-PAMAM-cholesterol) with 1,2,4 or 8 cholesteryl groups (named as P1, P2, P4, P8, respectively) were synthesized. Their chemical structures were characterized with ¹H NMR and mass spectrum (MALDI-TOF MS). The telodendrimers could self-assemble into micelles in aqueous solution, and encapsulate chemotherapeutic drug doxorubicin (DOX) and paclitaxel (PTX) for combination therapy. All the telodendrimers could encapsulate DOX with similar capability. However, their drug-loading capability of PTX is increased with the increasing number of cholesteryl groups. P8 exhibited much higher PTX loading efficiency than its counterparts. Thus, P8 was selected for further application of drug delivery in the paper. The drug-loading micellar nanoparticles (NPs) of P8 were spherical in shape and their diameters were less than 150 nm which were determined by dynamic light scattering measurements (DLS) and transmission electron microscope (TEM). In vitro drug release experiment demonstrated that P8 exhibited a controlled release manner for both DOX and PTX, and the two drugs were released simultaneously. In vitro cytotoxicity experiment further demonstrated that the co-delivery of DOX and PTX in P8 exhibited better anti-cancer efficiency than the delivery systems encapsulated with single drug (DOX or PTX). This indicates a synergistic effect. The co-delivery system showed potential in future anti-cancer treatment.     

DNA origami as a carrier for circumvention of drug resistance

Although a multitude of promising anti-cancer drugs have been developed over the past 50 years, effective delivery of the drugs to diseased cells remains a challenge. Recently, nanoparticles have been used as drug delivery vehicles due to their high delivery efficiencies and the possibility to circumvent cellular drug resistance. However, the lack of biocompatibility and inability to engineer spatially addressable surfaces for multi-functional activity remains an obstacle to their widespread use. Here we present a novel drug carrier system based on self-assembled, spatially addressable DNA origami nanostructures that confronts these limitations. Doxorubicin, a well-known anti-cancer drug, was non-covalently attached to DNA origami nanostructures through intercalation. A high level of drug loading efficiency was achieved, and the complex exhibited prominent cytotoxicity not only to regular human breast adenocarcinoma cancer cells (MCF?7), but more importantly to doxorubicin-resistant cancer cells, inducing a remarkable reversal of phenotype resistance. With the DNA origami drug delivery vehicles, the cellular internalization of doxorubicin was increased, which contributed to the significant enhancement of cell-killing activity to doxorubicin-resistant MCF?7 cells. Presumably, the activity of doxorubicin-loaded DNA origami inhibits lysosomal acidification, resulting in cellular redistribution of the drug to action sites. Our results suggest that DNA origami has immense potential as an efficient, biocompatible drug carrier and delivery vehicle in the treatment of cancer.     

Engineering hairy cellulose nanocrystals for chemotherapy drug capture

Cancer is one of the leading causes of death worldwide, affecting millions of people every year. Although chemotherapy remains one of the most common cancer treatments in the world, the severe side effects of chemotherapy drugs impose serious concerns to cancer patients. In many cases, the chemotherapy can be localized to maximize the drug effects; however, the drug systemic circulation induces undesirable side effects. Here, we have developed a highly efficient cellulose-based nanoadsorbent that can capture more than 6,000 milligrams of doxorubicin (DOX), one of the most widely used chemotherapy drugs, per gram of the adsorbent at physiological conditions. Such drug capture capacity is more than 3,200% higher than other nanoadsorbents, such as DNA-based platforms. We show how anionic hairy cellulose nanocrystals, also known as electrosterically stabilized nanocrystalline cellulose (ENCC), bind to positively charged drugs in human serum and capture DOX immediately without imposing any cytotoxicity and hemolytic effects. We elucidate how ENCC provides a remarkable platform for biodetoxification at varying pH, ionic strength, ion type, and protein concentration. The outcome of this research may pave the way for developing the next-generation in vitro and in vivo drug capture additives and devices.     

Thermal degradation of platinum(IV) precursors to antitumor drugs

Organoplatinum antitumor agents are very effective, broad-spectrum drugs used for the treatment of a variety of cancerous conditions. The two most prominent of these, Cisplatin [cis-diamminodichloroplatinum(II)] and Carboplatin [diammino(1,1-cyclobutanedicarboxylato)platinum(II)], are large scale commercial successes. The third, Oxaliplatin [((trans-1,2-diamminocyclohexane)oxalato)platinum(II)], is now commercially available. The administration of all these drugs is accompanied by severe side effects. For Cisplatin, the most debilitating of these is kidney damage and extreme nausea. Several approaches to generate drug-release formulations that might mitigate toxic side effects have been explored. Now, platinum(IV) compounds which are more inert than platinum(II) compounds, and consequently less toxic, but which may be reduced to platinum(II) species within the cell are being evaluated for effectiveness in the treatment of cancer. The thermal stability of several precursors to compounds of this kind has been examined by thermogravimetry. In general, these materials lose ligands sequentially to generate a residue of platinum. This behavior may be generally useful for the characterization of such materials.     

Cytotoxicity of a Lipid-Rich Extract from Native Mexican Avocado Seed (Persea americana var. drymifolia) on Canine Osteosarcoma D-17 Cells and Synergistic Activity with Cytostatic Drugs

Osteosarcoma is the most common malignant bone tumor in both children and dogs. It is an aggressive and metastatic cancer with a poor prognosis for long-term survival. The search for new anti-cancer drugs with fewer side effects has become an essential goal for cancer chemotherapy; in this sense, the bioactive compounds from avocado have proved their efficacy as cytotoxic molecules. The objective of this study was to determine the cytotoxic and antiproliferative effect of a lipid-rich extract (LEAS) from Mexican native avocado seed (Persea americana var. drymifolia) on canine osteosarcoma D-17 cell line. Also, the combined activity with cytostatic drugs was evaluated. LEAS was cytotoxic to D-17 cells in a concentration-dependent manner with an IC₅₀ = 15.5 µg/mL. Besides, LEAS induced caspase-dependent cell apoptosis by the extrinsic and intrinsic pathways. Moreover, LEAS induced a significant loss of mitochondrial membrane potential and increased superoxide anion production and mitochondrial ROS. Also, LEAS induced the arrest of the cell cycle in the G0/G1 phase. Finally, LEAS improved the cytotoxic activity of cisplatin, carboplatin, and in less extension, doxorubicin against the canine osteosarcoma cell line through a synergistic effect. In conclusion, avocado could be a potential source of bioactive molecules in the searching treatments for osteosarcoma.     

Use of the tubulin bound paclitaxel conformation for structure-based rational drug design

A new computational docking protocol has been developed and used in combination with conformational information inferred from REDOR-NMR experiments on microtubule bound 2-(p-fluorobenzoyl)paclitaxel to delineate a unique tubulin binding structure of paclitaxel. A conformationally constrained macrocyclic taxoid bearing a linker between the C-14 and C-3'N positions has been designed and synthesized to enforce this "REDOR-taxol" conformation. The novel taxoid SB-T-2053 inhibits the growth of MCF-7 and LCC-6 human breast cancer cells (wild-type and drug resistant) on the same order of magnitude as paclitaxel. Moreover, SB-T-2053 induces in vitro tubulin polymerization at least as well as paclitaxel, which directly validates our drug design process. These results open a new avenue for drug design of next generation taxoids and other microtubule-stabilizing agents based on the refined structural information of drug-tubulin complexes, in accordance with typical enzyme-inhibitor medicinal chemistry precepts.     

Recent advancements in the anticancer potentials of first row transition metal complexes

The frequently severe effects of currently utilized platinum-based complexes have prompted researchers to develop less toxic transition metal based anticancer drugs. Transition metal complexes have recently gained considerable attention as promising anticancer agents due to their efficient drug design and fast optimisation. Some transition metal complexes displayed better anticancer activity than cis-platin. This led to the transition metal complexes for clinical application of chemotherapeutic drugs for cancer therapy. Cytotoxicity of the complexes has been evaluated on the basis of their IC₅₀ values. In this review, we have focussed on recent findings about the anticancer mechanism of action of first row transition metal complexes during the last ten years.     

铂类抗癌药物-纳米金载药体系的研究进展

铂类抗癌药物凭借着独特的作用机制,已成为临床治疗中应用广泛的抗癌药物之一。但由于存在较为严重的毒副作用、耐药性等问题,限制了其在临床上的使用。为了改善它的这些不足,更大限度提高药物的生物利用度并尽量减少其副作用,使用靶向给药体系改变铂类药物体内递送方式受到了广泛关注。其中铂药-纳米金载药体系因其较大的载药量、易于修饰改造、癌细胞高通透性和滞留效应、无免疫原性等显著的特点而受到研究者们的重视,本文主要介绍近十年来铂类抗癌药物-纳米金载药体系的研究进展。     

Remotely controlled electro-responsive on-demand nanotherapy based on amine-modified graphene oxide for synergistic dual drug delivery

This study focuses on the development of a new electric field responsive graphene oxide (GO) nanoparticle system for on-demand drug delivery. Today, GO is an attractive option adopted in various biological applications for its exclusive features such as flexibility, conductiveness, cost-effectiveness, and external stimuli-responsive nature. It is usual to utilize multiple drugs in cancer treatment. This kind of therapy has lesser side-effects, drug resistance, and is more effective than utilizing only one drug. This study aims to determine low-voltage-controlled dual drug (aspirin and doxorubicin) release from GO surface. Here, we have demonstrated how to control the drug release rate remotely with a handy mobile phone, with zero passive release at idle time. In addition, the study focused to estimate the synergism of aspirin with doxorubicin in the release mechanism from GO in the presence of external voltage, using the spectroscopic method. Moreover, we observed aspirin- and doxorubicin-induced synergistic antitumor activity in MDA-MB 231 (breast cancer cell) in vitro. Thus, our study presents a noble combination of aspirin and doxorubicin that could be utilized for remotely controlled on-demand drug delivery for triple negative breast cancer treatment, using GO as a carrier.     

Experimental design for copper cementation process in fixed bed reactor using two-level factorial design

This work deals with cementation of copper onto iron grid in a fixed bed reactor. The influence of several parameters is studied, namely: initial concentration of copper [Cu²⁺]₀, temperature and flow rate. Moreover, their influence on the copper cementation reaction is investigated statistically by the experimental design in view of industrial application. The estimation and the comparison of the parameter’s effects are realized by using two-level factorial design. The analysis of these effects permits to state that the most influential factor is initial concentration of copper [Cu²⁺]₀ with an effect of (+2.4566), the second in the order is the temperature with an effect of (+0.18959), the third is the flow rate of the electrolytic solution with an effect of (?0.4226). The significance interactions found by the design of experiments are between initial concentrations of copper ions–flow rate (x₁x₃) with an effect (b₁₃ = +0.6965).     

Investigating the Role of Obesity in Prostate Cancer and Identifying Biomarkers for Drug Discovery: Systems Biology and Deep Learning Approaches

Prostate cancer (PCa) is the second most frequently diagnosed cancer for men and is viewed as the fifth leading cause of death worldwide. The body mass index (BMI) is taken as a vital criterion to elucidate the association between obesity and PCa. In this study, systematic methods are employed to investigate how obesity influences the noncutaneous malignancies of PCa. By comparing the core signaling pathways of lean and obese patients with PCa, we are able to investigate the relationships between obesity and pathogenic mechanisms and identify significant biomarkers as drug targets for drug discovery. Regarding drug design specifications, we take drug–target interaction, drug regulation ability, and drug toxicity into account. One deep neural network (DNN)-based drug–target interaction (DTI) model is trained in advance for predicting drug candidates based on the identified biomarkers. In terms of the application of the DNN-based DTI model and the consideration of drug design specifications, we suggest two potential multiple-molecule drugs to prevent PCa (covering lean and obese PCa) and obesity-specific PCa, respectively. The proposed multiple-molecule drugs (apigenin, digoxin, and orlistat) not only help to prevent PCa, suppressing malignant metastasis, but also result in lower production of fatty acids and cholesterol, especially for obesity-specific PCa.