Bioinformatic Analysis of the Nicotinamide Binding Site in Poly(ADP-Ribose) Polymerase Family Proteins

The PARP family consists of 17 members with diverse functions, including those related to cancer cells’ viability. Several PARP inhibitors are of great interest as innovative anticancer drugs, but they have low selectivity towards distinct PARP family members and exert serious adverse effects. We describe a family-wide study of the nicotinamide (NA) binding site, an important functional region in the PARP structure, using comparative bioinformatic analysis and molecular modeling. Mutations in the NA site and D-loop mobility around the NA site were identified as factors that can guide the design of selective PARP inhibitors. Our findings are of particular importance for the development of novel tankyrase (PARPs 5a and 5b) inhibitors for cancer therapy.

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ID: 4001 Nanoparticle-based Cancer Therapy

Biomedical Research and Therapy ◽

10.15419/bmrat.v4is.211 ◽

2017 ◽

Vol 4 (S) ◽

pp. 2

Author(s):

Fuyu Tamanoi

Keyword(s):

Magnetic Field ◽

Iron Oxide ◽

Cancer Therapy ◽

Cancer Cells ◽

Anticancer Drugs ◽

Tumor Targeting ◽

Two Photon ◽

Pore Opening ◽

Oscillating Magnetic Field ◽

The Way

Advances in Nanotechnology have led to the development of a variety of nanomaterials that are changing the way cancer therapy is carried out. A particularly important example is nanoparticle that can carry cargo to tumor. We are using mesoporous silica nanoparticles (MSNs) for cancer therapy. MSNs contain thousands of pores that provide storage space for anticancer drugs. These materials are biocompatible and safe. In addition, we have recently introduced biodegradability into MSNs. We have shown that MSNs exhibit excellent tumor targeting capability in two different animal model systems (chicken egg tumor model and mouse xenografts). This tumor targeting capability is partly due to its small size; these nano-sized particles can accumulate in tumor due to leaky tumor vasculature. In addition, we have carried out surface modifications to attach ligands that bind receptors present on the surface of cancer cells. For example, folate was attached to the surface that enables binding to folate receptors overexpressed on cancer cells. We have also conferred controlled anticancer drug release capability to MSNs in collaboration with Fraser Stoddart and Jeff Zink. This was accomplished by attaching nanovalves at the opening of the pores. Rotaxanes and pseudorotaxanes are used to prepare nanovalves. These chemical compounds consist of a stalk and a moving part. When the moving part is close to the pore opening, the nanovalve is closed. On the other hand, when the moving part is located away from the pore opening, the nanovalve is closed. In this way, the nanovalve provides an open and close function so that controlled release of anticancer drugs can be carried out. Light activated nanovalves were developed by incorporating azobenzene into nanovalves. Azobenzene changes conformation upon light exposure and this conformational change opens the nanovalve releasing anticancer drugs in a power and exposure time dependent manner. More recently, this system was modified by incorporating two-photon dyes that can capture energy from two-photon light and transfer to azobenzene to drive the release of anticancer drugs. This enables the system to work with tissue penetrating two-photon light. We have also developed nanoparticles that respond to oscillating magnetic field. This system was developed using MSNs that contain iron oxide core. Because of superparamagnetic property of iron oxide, the internal temperature of such nanoparticles increases when exposed to oscillating magnetic field. This temperature increase drives opening of nanovalves that are particularly designed for this purpose. Development of nanoparticles that respond to external cues such as light and magnetic field may change the way cancer therapy is carried out. Implications on the future of cancer therapy will be discussed.

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Unimolecular micelles of pH-responsive star-like copolymers for co-delivery of anticancer drugs and small-molecular photothermal agents: a new drug-carrier for combinational chemo/photothermal cancer therapy

Journal of Materials Chemistry B ◽

10.1039/c7tb01657c ◽

2017 ◽

Vol 5 (43) ◽

pp. 8514-8524 ◽

Cited By ~ 12

Author(s):

Tao Jia ◽

Shuo Huang ◽

Cangjie Yang ◽

Mingfeng Wang

Keyword(s):

Cancer Therapy ◽

Cancer Cells ◽

Therapeutic Effect ◽

Anticancer Drugs ◽

Drug Carrier ◽

Ph Responsive ◽

New Drug

Robust unimolecular micelles of amphiphilic pH-responsive starlike copolymers that carry anticancer drugs and photothermal agents show enhanced therapeutic effect against cancer cells.

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Liposomes as target delivery of antitumor drugs

Russian Journal of Biotherapy ◽

10.17650/1726-9784-2016-15-2-90-96 ◽

2016 ◽

Vol 15 (2) ◽

pp. 90-96 ◽

Cited By ~ 2

Author(s):

A. O. Raikov ◽

A. . Hashem ◽

M. A. Baryshnikova

Keyword(s):

Cancer Therapy ◽

Cancer Cells ◽

Anticancer Drugs ◽

Antitumor Drugs ◽

Drug Formulations ◽

Target Delivery ◽

Research Status ◽

Selective Delivery

Target delivery of antitumor drugs to cancer cells seems to be the very promising way of cancer therapy. The study on the application of immunoliposomes as nanocontainers for anticancer drugs started in the 90-ies. Immunoliposomal drug formulations of antitumor preparations have some advantages over traditional forms of drugs: lipid capsule reduces toxicity of drug due to the selective delivery to tumor and improves its bioavailability. However, despite these benefits, at present immunoliposomal drugs application is limited in the clinic. This review discusses current research status in field of development immunoliposomes and the possible targets for anticancer immuno-liposomes.

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Cytotoxic Effect of the Combination of Gemcitabine and Atorvastatin Loaded in Microemulsion on the HCT116 Colon Cancer Cells

International Journal of Pharmaceutical and Clinical Research ◽

10.25258/ijpcr.v9i2.8298 ◽

2017 ◽

Vol 9 (2) ◽

Cited By ~ 1

Author(s):

Mayson H. Alkhatib ◽

Dalal Al-Saedi ◽

Wadiah S. Backer

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Anticancer Drugs ◽

Therapeutic Potential ◽

Morphological Changes ◽

In Vitro Study ◽

Colon Cancer Cells ◽

Apoptosis Detection ◽

Hct116 Cells

The combination of anticancer drugs in nanoparticles has great potential as a promising strategy to maximize efficacies by eradicating resistant, reduce the dosage of the drug and minimize toxicities on the normal cells. Gemcitabine (GEM), a nucleoside analogue, and atorvastatin (ATV), a cholesterol lowering agent, have shown anticancer effect with some limitations. The objective of this in vitro study was to evaluate the antitumor activity of the combination therapy of GEM and ATVencapsulated in a microemulsion (ME) formulation in the HCT116 colon cancer cells. The cytotoxicity and efficacy of the formulation were assessed by the 3- (4,5dimethylthiazole-2-yl)-2,5-diphyneltetrazolium bromide (MTT) assay. The mechanism of cell death was examined by observing the morphological changes of treated cells under light microscope, identifying apoptosis by using the ApopNexin apoptosis detection kit, and viewing the morphological changes in the chromatin structure stained with 4′,6-diamidino-2-phenylindole (DAPI) under the inverted fluorescence microscope. It has been found that reducing the concentration of GEM loaded on ME (GEM-ME) from 5μM to 1.67μM by combining it with 3.33μM of ATV in a ME formulation (GEM/2ATV-ME) has preserved the strong cytotoxicity of GEM-ME against HCT116 cells. The current study proved that formulating GEM with ATV in ME has improved the therapeutic potential of GEM and ATV as anticancer drugs.

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Hybrid Compounds & Oxidative Stress Induced Apoptosis in Cancer Therapy

Current Medicinal Chemistry ◽

10.2174/0929867325666180719145819 ◽

2020 ◽

Vol 27 (13) ◽

pp. 2118-2132 ◽

Cited By ~ 5

Author(s):

Aysegul Hanikoglu ◽

Hakan Ozben ◽

Ferhat Hanikoglu ◽

Tomris Ozben

Keyword(s):

Oxidative Stress ◽

Drug Resistance ◽

Side Effects ◽

Cancer Therapy ◽

Tumor Cells ◽

Anticancer Drugs ◽

Chemotherapeutic Agents ◽

Oxidation Reactions ◽

Hybrid Compounds ◽

Induced Apoptosis

: Elevated Reactive Oxygen Species (ROS) generated by the conventional cancer therapies and the endogenous production of ROS have been observed in various types of cancers. In contrast to the harmful effects of oxidative stress in different pathologies other than cancer, ROS can speed anti-tumorigenic signaling and cause apoptosis of tumor cells via oxidative stress as demonstrated in several studies. The primary actions of antioxidants in cells are to provide a redox balance between reduction-oxidation reactions. Antioxidants in tumor cells can scavenge excess ROS, causing resistance to ROS induced apoptosis. Various chemotherapeutic drugs, in their clinical use, have evoked drug resistance and serious side effects. Consequently, drugs having single-targets are not able to provide an effective cancer therapy. Recently, developed hybrid anticancer drugs promise great therapeutic advantages due to their capacity to overcome the limitations encountered with conventional chemotherapeutic agents. Hybrid compounds have advantages in comparison to the single cancer drugs which have usually low solubility, adverse side effects, and drug resistance. This review addresses two important treatments strategies in cancer therapy: oxidative stress induced apoptosis and hybrid anticancer drugs.

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Lipid-based Nanoplatforms in Cancer Therapy: Recent Advances and Applications

Current Cancer Drug Targets ◽

10.2174/1568009620666200115160805 ◽

2020 ◽

Vol 20 (4) ◽

pp. 271-287 ◽

Cited By ~ 2

Author(s):

Kuldeep Rajpoot

Keyword(s):

Drug Delivery ◽

Cancer Therapy ◽

Adverse Effects ◽

Targeted Drug Delivery ◽

Tumor Therapy ◽

Cancer Therapies ◽

Medication Delivery ◽

Lipid Nanocarriers ◽

Targeted Drug ◽

Drug Nanocarriers

Though modern available cancer therapies are effective, they possess major adverse effects, causing non-compliance to patients. Furthermore, the majority of the polymeric-based medication platforms are certainly not universally acceptable, due to their several restrictions. With this juxtaposition, lipid-based medication delivery systems have appeared as promising drug nanocarriers to replace the majority of the polymer-based products because they are in a position to reverse polymer as well as, drug-associated restrictions. Furthermore, the amalgamation of the basic principle of nanotechnology in designing lipid nanocarriers, which are the latest form of lipid carriers, has tremendous chemotherapeutic possibilities as tumor-targeted drug-delivery pertaining to tumor therapy. Apart from this, it is reported that nearly 40% of the modern medication entities are lipophilic. Moreover, research continues to be efficient in attaining a significant understanding of the absorption and bioavailability of the developed lipids systems.

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Hyaluronan based Multifunctional Nano-carriers for Combination Cancer Therapy

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200922113846 ◽

2020 ◽

Vol 20 ◽

Author(s):

Menghan Gao ◽

Hong Deng ◽

Weiqi Zhang

Keyword(s):

Cancer Therapy ◽

Combination Therapy ◽

Cancer Cells ◽

Drug Loading ◽

Tumor Therapy ◽

Drug Carriers ◽

Functional Sites ◽

Therapeutic Modalities ◽

Combination Cancer Therapy ◽

Targeting Strategy

: Hyaluronan (HA) is a natural linear polysaccharide that has excellent hydrophilicity, biocompatibility, biodegradability, and low immunogenicity, making it one of the most attractive biopolymers used for biomedical researches and applications. Due to the multiple functional sites on HA and its intrinsic affinity for CD44, a receptor highly expressed on various cancer cells, HA has been widely engineered to construct different drug-loading nanoparticles (NPs) for CD44- targeted anti-tumor therapy. When a cocktail of drugs is co-loaded in HA NP, a multifunctional nano-carriers could be obtained, which features as a highly effective and self-targeting strategy to combat the cancers with CD44 overexpression. The HA-based multidrug nano-carriers can be a combination of different drugs, various therapeutic modalities, or the integration of therapy and diagnostics (theranostics). Up to now, there are many types of HA-based multidrug nano-carriers constructed by different formulation strategies including drug co-conjugates, micelles, nano-gels and hybrid NP of HA and so on. This multidrug nano-carrier takes the full advantages of HA as NP matrix, drug carriers and targeting ligand, representing a simplified and biocompatible platform to realize the targeted and synergistic combination therapy against the cancers. In this review, recent progresses about HA-based multidrug nano-carriers for combination cancer therapy are summarized and its potential challenges for translational applications have been discussed.

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Synthesis, Anti-proliferative Evaluation, and Molecular Docking Studies of 3-(alkylthio)-5,6-diaryl-1,2,4-triazines as Tubulin Polymerization Inhibitors

Letters in Drug Design & Discovery ◽

10.2174/1570180815666180727114216 ◽

2019 ◽

Vol 16 (11) ◽

pp. 1194-1201 ◽

Cited By ~ 3

Author(s):

Farhad Saravani ◽

Ebrahim Saeedian Moghadam ◽

Hafezeh Salehabadi ◽

Seyednasser Ostad ◽

Morteza Pirali Hamedani ◽

...

Keyword(s):

Molecular Modeling ◽

Cytotoxic Activity ◽

Binding Site ◽

Cell Line ◽

Cell Lines ◽

Tubulin Polymerization ◽

Adenocarcinoma Cell Line ◽

Adenocarcinoma Cell ◽

Colchicine Binding Site ◽

Anti Cancer

Background: The role of microtubules in cell division and signaling, intercellular transport, and mitosis has been well known. Hence, they have been targeted for several anti-cancer drugs. Methods: A series of 3-(alkylthio)-5,6-diphenyl-1,2,4-triazines were prepared and evaluated for their cytotoxic activities in vitro against three human cancer cell lines; human colon carcinoma cells HT-29, human breast adenocarcinoma cell line MCF-7, human Caucasian gastric adenocarcinoma cell line AGS as well as fibroblast cell line NIH-3T3 by MTT assay. Docking simulation was performed to insert these compounds into the crystal structure of tubulin at the colchicine binding site to determine a probable binding model. Compound 5d as the most active compound was selected for studying of microtubule disruption. Results: Compound 5d showed potent cytotoxic activity against all cell lines. The molecular modeling study revealed that some derivatives of triazine strongly bind to colchicine binding site. The tubulin polymerization assay kit showed that the cytotoxic activity of 5d may be related to inhibition of tubulin polymerization. Conclusion: The cytotoxicity and molecular modeling study of the synthesized compounds with their inhibition activity in tubulin polymerization demonstrate the potential of triazine derivatives for development of new anti-cancer agents.

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