scholarly journals Computer-Aided Design for Identifying Anticancer Targets in Genome-Scale Metabolic Models of Colon Cancer

Biology ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1115
Author(s):  
Chao-Ting Cheng ◽  
Tsun-Yu Wang ◽  
Pei-Rong Chen ◽  
Wu-Hsiung Wu ◽  
Jin-Mei Lai ◽  
...  
Keyword(s):  
Side Effects ◽  
Computer Aided Design ◽  
Fitness Function ◽  
Cholesterol Biosynthesis ◽  
Differential Evolution Algorithm ◽  
Fuzzy Optimization ◽  
Drug Efficacy ◽  
Pentose Phosphate ◽  
Normal Cells ◽  
Development Costs

The efficient discovery of anticancer targets with minimal side effects is a major challenge in drug discovery and development. Early prediction of side effects is key for reducing development costs, increasing drug efficacy, and increasing drug safety. This study developed a fuzzy optimization framework for Identifying AntiCancer Targets (IACT) using constraint-based models. Four objectives were established to evaluate the mortality of treated cancer cells and to minimize side effects causing toxicity-induced tumorigenesis on normal cells and smaller metabolic perturbations. Fuzzy set theory was applied to evaluate potential side effects and investigate the magnitude of metabolic deviations in perturbed cells compared with their normal counterparts. The framework was applied to identify not only gene regulator targets but also metabolite- and reaction-centric targets. A nested hybrid differential evolution algorithm with a hierarchical fitness function was applied to solve multilevel IACT problems. The results show that the combination of a carbon metabolism target and any one-target gene that participates in the sphingolipid, glycerophospholipid, nucleotide, cholesterol biosynthesis, or pentose phosphate pathways is more effective for treatment than one-target inhibition is. A clinical antimetabolite drug 5-fluorouracil (5-FU) has been used to inhibit synthesis of deoxythymidine-5′-triphosphate for treatment of colorectal cancer. The computational results reveal that a two-target combination of 5-FU and a folate supplement can improve cell viability, reduce metabolic deviation, and reduce side effects of normal cells.

Molecular Studies on Novel Antitumor Bis 1,4-Dihydropyridine Derivatives Against Lung Carcinoma and their Limited Side Effects on Normal Melanocytes

2019 ◽  
Vol 18 (15) ◽  
pp. 2156-2168 ◽  
Author(s):  
Magda F. Mohamed ◽  
Nada S. Ibrahim ◽  
Ahmed H.M. Elwahy ◽  
Ismail A. Abdelhamid
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Cancer Cells ◽  
Cell Line ◽  
Lung Carcinoma ◽  
Carcinoma Cell ◽  
Normal Cells ◽  
Lung Carcinoma Cell Line ◽  
Molecular Studies ◽  
Dihydropyridine Derivatives

Background: Cancer is a complex genetic disease which is characterized by an abnormal cell growth, invasion and spreading to other parts of the body. There are several factors that lead to cancer by causing DNA damage and the impairment of its repair. Treatment of cancer using the chemotherapeutic drugs have adverse side effects such as toxicity as they lose their specificity toward cancer cells and affect also normal cells. Moreover, the cancer cells can resist the chemotherapeutic agents and make them ineffective. For these reasons, much attentions have been paid to develop new drugs with limited side effects on normal cells and to diminish cancer resistance to drug chemotherapy. Recently, some 1,4-dihydropyridine derivatives were reported to act as Multi-Drug Resistance (MDR) modulators that inhibit p-glycoprotein which is responsible for the inability of drugs to enter the cancer cells. Also 1,4-DHPs have antimutagenic properties against chemicals via modulating DNA repair when studied on drosophila. Objective: The objective of this study is the synthesis of bis 1,4-DHPs incorporating ester as well as ether linkages and evaluate the anticancer activity of new compounds for synergistic purpose. Different genetic tools were used in an attempt to know the mechanism of action of this compound against lung cancer. Method: An efficient one pot synthesis of bis 1,4-DHPs using 3-aminocrotononitrile and bis(aldehydes) has been developed. The cytotoxic effect against human cell lines MCF7, and A549 cell lines was evaluated. Results: All compounds exhibited better cytotoxicity toward lung carcinoma cells than breast cancer cells. With respect to lung carcinoma cell line (A549), compound 10 was the most active compound and the three other compounds 7, 8, and 9 showed comparable IC50 values. In case of breast cancer cell line (MCF7), the most active one was compound 7, while compound 8 recorded the least activity. Conclusion: we have developed an efficient method for the synthesis of novel bis 1,4-dihydropyridine derivatives incorporating ester or ether linkage. All compounds showed better cytotoxicity results against A549 than MCF7, so that lung carcinoma cell line was chosen to perform the molecular studies on it. The results showed that all compounds (7, 8, 9 and 10) caused cell cycle arrest at G1 phase. The molecular docking study on CDK2 confirmed the results of cell cycle assay which showed good binding energy between the compounds and the active site of enzyme indicating the inhibition of the enzyme.

Synthesis and Investigation of Therapeutic Potential of Isoform-Specific HDAC8 Inhibitors for the Treatment of Cutaneous T Cell Lymphoma

2019 ◽  
Vol 19 (7) ◽  
pp. 916-934 ◽  
Author(s):  
Appavoo Umamaheswari ◽  
Ayarivan Puratchikody ◽  
Natarajan Hari
Keyword(s):  
Side Effects ◽  
Inhibitory Activity ◽  
Hydroxamic Acid ◽  
Histone Deacetylase Inhibitors ◽  
Therapeutic Potential ◽  
In Vitro Assays ◽  
Normal Cells ◽  
Standard Drug ◽  
In Silico Studies ◽  
Hdac8 Inhibitors

Background:The available treatment option for any type of cancer including CTCL is chemotherapy and radiation therapy which indiscriminately persuade on the normal cells. One way out for selective destruction of CTCL cells without damaging normal cells is the use of histone deacetylase inhibitors (HDACi). Despite promising results in the treatment of CTCL, these HDACi have shown a broadband inhibition profile, moderately selective for one HDAC class but not for a particular isotype. The prevalence of drug-induced side effects leaves open a narrow window of speculation that the decreased therapeutic efficacy and observed side effects may be most likely due to non specific HDAC isoform inhibition. The aim of this paper is to synthesis and evaluates HDAC8 isoform specific inhibitors.Methods:Based on the preliminary report on the design and in silico studies of 52 hydroxamic acid derivatives bearing multi-substituent heteroaromatic rings with chiral amine linker, five compounds were shortlisted and synthesized by microwave assisted approach and high yielding synthetic protocol. A series of in vitro assays in addition to HDAC8 inhibitory activity was used to evaluate the synthesised compounds.Results:Inhibitors 1e, 2e, 3e, 4e and 5e exerted the anti-proliferative activities against CTCL cell lines at 20- 100 µM concentrations. Both the pyrimidine- and pyridine-based probes exhibited μM inhibitory activity against HDAC8. The pyrimidine-based probe 1e displayed remarkable HDAC8 selectivity superior to that of the standard drug, SAHA with an IC50 at 0.1µM.Conclusion:Our study demonstrated that simple modifications at different portions of pharmacophore in the hydroxamic acid analogues are effective for improving both HDAC8 inhibitory activity and isoform selectivity. Potent and highly isoform-selective HDAC8 inhibitors were identified. These findings would be expedient for further development of HDAC8-selective inhibitors.

scholarly journals Polypharmacy and Malnutrition Management of Elderly Perioperative Patients with Cancer: A Systematic Review

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1961
Author(s):  
Eiji Kose ◽  
Hidetaka Wakabayashi ◽  
Nobuhiro Yasuno
Keyword(s):  
Side Effects ◽  
Cancer Cachexia ◽  
Drug Effects ◽  
Drug Efficacy ◽  
Nutritional Management ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Drug Induced ◽  
Anabolic Resistance ◽  
Patients With Cancer ◽  
The Impact

Malnutrition, which commonly occurs in perioperative patients with cancer, leads to decreased muscle mass, hypoalbuminemia, and edema, thereby increasing the patient’s risk of various complications. Thus, the nutritional management of perioperative patients with cancer should be focused on to ensure that surgical treatment is safe and effective, postoperative complications are prevented, and mortality is reduced. Pathophysiological and drug-induced factors in elderly patients with cancer are associated with the risk of developing malnutrition. Pathophysiological factors include the effects of tumors, cachexia, and anorexia of aging. Metabolic changes, such as inflammation, excess catabolism, and anabolic resistance in patients with tumor-induced cancer alter the body’s ability to use essential nutrients. Drug-induced factors include the side effects of anticancer drugs and polypharmacy. Drug–drug, drug–disease, drug–nutrient, and drug–food interactions can significantly affect the patient’s nutritional status. Furthermore, malnutrition may affect pharmacokinetics and pharmacodynamics, potentiate drug effects, and cause side effects. This review outlines polypharmacy and malnutrition, the impact of malnutrition on drug efficacy, drug–nutrient and drug–food interactions, and intervention effects on polypharmacy or cancer cachexia in elderly perioperative patients with cancer.

Natural-Derived Molecules as a Potential Adjuvant in Chemotherapy: Normal Cell Protectors and Cancer Cell Sensitizers

2021 ◽  
Vol 21 ◽  
Author(s):  
Rajib Hossain ◽  
Muhammad Torequl Islam ◽  
Mohammad S. Mubarak ◽  
Divya Jain ◽  
Rasel Khan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Side Effects ◽  
Cancer Cells ◽  
Chemotherapeutic Agents ◽  
Polyphenolic Compounds ◽  
Anticancer Effect ◽  
Anticancer Activities ◽  
Normal Cells ◽  
Anti Cancer ◽  
Global Threat

Background: Cancer is a global threat to humans and a leading cause of death worldwide. Cancer treatment includes, among other things, the use of chemotherapeutic agents, compounds that are vital for treating and preventing cancer. However, chemotherapeutic agents produce oxidative stress along with other side effects that would affect the human body. Objective: To reduce the oxidative stress of chemotherapeutic agents in cancer and normal cells by naturally derived compounds with anti-cancer properties, and protect normal cells from the oxidation process. Therefore, the need to develop more potent chemotherapeutics with fewer side effects has become increasingly important. Method: Recent literature dealing with the antioxidant and anticancer activities of the naturally naturally-derived compounds: morin, myricetin, malvidin, naringin, eriodictyol, isovitexin, daidzein, naringenin, chrysin, and fisetin has been surveyed and examined in this review. For this, data were gathered from different search engines, including Google Scholar, ScienceDirect, PubMed, Scopus, Web of Science, Scopus, and Scifinder, among others. Additionally, several patient offices such as WIPO, CIPO, and USPTO were consulted to obtain published articles related to these compounds. Result: Numerous plants contain flavonoids and polyphenolic compounds such as morin, myricetin, malvidin, naringin, eriodictyol, isovitexin, daidzein, naringenin, chrysin, and fisetin, which exhibit ‎antioxidant, anti-inflammatory, and anti-carcinogenic actions via several mechanisms. These compounds show sensitizers of cancer cells and protectors of healthy cells. Moreover, these compounds can reduce oxidative stress, which is accelerated by chemotherapeutics and exhibit a potent anticancer effect on cancer cells. Conclusions: Based on these findings, more research is recommended to explore and evaluate such flavonoids and polyphenolic compounds.

Targeting vitamin E TPGS–cantharidin conjugate nanoparticles for colorectal cancer therapy

RSC Advances ◽  
2015 ◽  
Vol 5 (66) ◽  
pp. 53846-53856 ◽  
Author(s):  
Shihou Sheng ◽  
Tao Zhang ◽  
Shijie Li ◽  
Jun Wei ◽  
Guangjun Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Delivery ◽  
Vitamin E ◽  
Chinese Medicine ◽  
Side Effects ◽  
Cancer Therapy ◽  
Traditional Chinese Medicine ◽  
Drug Efficacy ◽  
Vitamin E Tpgs ◽  
Colorectal Cancer Cells

A traditional Chinese medicine cantharidin which was previously found to be effective on colorectal cancer cells was translated into nanoparticles for drug delivery to reduce its side effects and enhance its drug efficacy.

scholarly journals What is associated with increased side effects and lower perceived efficacy following switching to a generic medicine? A New Zealand cross-sectional patient survey

BMJ Open ◽  
2018 ◽  
Vol 8 (10) ◽  
pp. e023667 ◽  
Author(s):  
Kate MacKrill ◽  
Keith J Petrie
Keyword(s):  
New Zealand ◽  
Side Effects ◽  
Generic Version ◽  
Drug Efficacy ◽  
Patient Survey ◽  
Generic Medicine ◽  
Cross Sectional Survey ◽  
Online Questionnaire ◽  
Cross Sectional ◽  
Perceived Efficacy

ObjectiveFollowing a switch from either a generic or branded antidepressant (venlafaxine) to a new generic, we investigated the factors associated with a preference for branded medicines, side effects reported following switching and efficacy ratings of the new generic drug.DesignA cross-sectional survey of patients switched to a new generic.SettingPatients accessing venlafaxine information online from the New Zealand government pharmaceuticals funding website.Participants310 patients, comprising 205 originally on branded venlafaxine and 105 previously taking a generic version.Main outcome measuresAn online questionnaire assessing demographic factors, perceived sensitivity to medicines, trust in pharmaceutical agencies, sources of switch information, preference for branded medicine, new medicine perceptions, side effects and efficacy ratings.ResultsPreference for branded medicine was significantly stronger in older patients (OR=1.04, 95% CI 1.01 to 1.05), those taking branded venlafaxine (OR=2.02, 95% CI 1.13 to 3.64) and patients with a higher perceived sensitivity to medicine (OR=1.23, 95% CI 1.06 to 1.19). Different factors predicted side effects in those switching from the branded and those switching from the generic venlafaxine. Trust in pharmaceutical agencies and the number of side effects were significant predictors of efficacy ratings of the new generic in both patients switching from a branded and those switching from a generic version of venlafaxine.ConclusionsIn patients switching from a branded medicine and those already taking a generic, different demographic and psychological factors are associated with preference for branded medicine, side effect reporting and perceived efficacy of the new drug. When switching to new generic, there appears to be a close bidirectional relationship between the experience of side effects and perceived drug efficacy. Trust in pharmaceutical agencies impacts directly on perceived efficacy and increasing such trust could reduce the nocebo response following a generic switch.

Host-cell-assisted construction of folate-engineered nanocarrier based on viral light particle for targeted cancer therapy

Nanoscale ◽  
2021 ◽  
Author(s):  
Cheng Lv ◽  
Jian Ao ◽  
Ji Wang ◽  
Man Tang ◽  
An-An Liu ◽  
...  
Keyword(s):  
Side Effects ◽  
Cancer Therapy ◽  
Host Cell ◽  
Tumor Targeting ◽  
Light Particle ◽  
Targeted Cancer Therapy ◽  
Normal Cells ◽  
Specific Tumor

Targeted cancer therapy has aroused broad interests of researchers due to its accuracy in specific tumor targeting and few side effects on normal cells. In the last decades, oncolytic viral...

Pharmacogenomics Genome Wise Association Clinical Studies

2015 ◽  
pp. 218-233
Author(s):  
Udayaraja GK
Keyword(s):  
Side Effects ◽  
Drug Toxicity ◽  
Dose Adjustment ◽  
Drug Efficacy ◽  
New Drugs ◽  
Genomic Research ◽  
Drug Doses ◽  
Genetic Makeup ◽  
Trial And Error Method ◽  
Error Method

Pharmacogenomics deals with drug responses in individual based on genetic variation in genome. Based on genetic variations, drugs may produce more or less therapeutic effect, and same way in side effects also. Physicians can use information about your genetic makeup to choose those drugs and drug doses to get better therapy. Optimizing drug therapy and rational dose adjustment with respect to genetic makeup will maximize drug efficacy and minimal adverse effects. This broken traditional ‘trial and error' method of ‘one drug fits all', and ‘one dose fits all' which contributing to 25–50% of drug toxicity or treatment failures. This will contribute to improve the ways in which existing drugs are used, genomic research will lead to drug development to produce new drugs that are highly effective without serious side effects. This approach to bring personalized medicine more practice and drug combinations are optimized for each individual' genetic makeup.

scholarly journals PROMISCUOUS 2.0: a resource for drug-repositioning

2020 ◽  
Vol 49 (D1) ◽  
pp. D1373-D1380
Author(s):  
Kathleen Gallo ◽  
Andrean Goede ◽  
Andreas Eckert ◽  
Barbara Moahamed ◽  
Robert Preissner ◽  
...  
Keyword(s):  
Side Effects ◽  
Small Molecules ◽  
User Experience ◽  
Drug Target ◽  
Drug Repositioning ◽  
Dynamic Network ◽  
Structural Similarity ◽  
New Drugs ◽  
Entry Level ◽  
Development Costs

Abstract The development of new drugs for diseases is a time-consuming, costly and risky process. In recent years, many drugs could be approved for other indications. This repurposing process allows to effectively reduce development costs, time and, ultimately, save patients’ lives. During the ongoing COVID-19 pandemic, drug repositioning has gained widespread attention as a fast opportunity to find potential treatments against the newly emerging disease. In order to expand this field to researchers with varying levels of experience, we made an effort to open it to all users (meaning novices as well as experts in cheminformatics) by significantly improving the entry-level user experience. The browsing functionality can be used as a global entry point to collect further information with regards to small molecules (∼1 million), side-effects (∼110 000) or drug-target interactions (∼3 million). The drug-repositioning tab for small molecules will also suggest possible drug-repositioning opportunities to the user by using structural similarity measurements for small molecules using two different approaches. Additionally, using information from the Promiscuous 2.0 Database, lists of candidate drugs for given indications were precomputed, including a section dedicated to potential treatments for COVID-19. All the information is interconnected by a dynamic network-based visualization to identify new indications for available compounds. Promiscuous 2.0 is unique in its functionality and is publicly available at http://bioinformatics.charite.de/promiscuous2.

Automatic Circuit Design of CMOS Miller OTA Using Cuckoo Search Algorithm

2020 ◽  
Vol 11 (1) ◽  
pp. 36-44
Author(s):  
Pankaj P. Prajapati ◽  
Mihir V. Shah
Keyword(s):  
Circuit Design ◽  
Computer Aided Design ◽  
Search Algorithm ◽  
Fitness Function ◽  
Large Fraction ◽  
Cuckoo Search ◽  
Cmos Technology ◽  
Experimental Simulation ◽  
Automatic Design ◽  
Simulation Results

The circuit design of the CMOS based analog part of a mixed-signal integrated circuit (IC) needs a large fraction of the overall design cycle time. The automatic design of an analog circuit is inevitable, seeing recently development of System-on-Chip (SOC) design. This brings about the need to develop computer aided design (CAD) tools for automatic design of CMOS based analog circuits. In this article, a Cuckoo Search (CS) algorithm is presented for automatic design of a CMOS Miller Operational Transconductance Amplifier (OTA). The source code of the CS algorithm is developed using the C language. The Ngspice circuit simulator has been used as a fitness function creator and evaluator. A script file is written to provide an interface between the CS algorithm and the Ngspice simulator. BSIM3v3 MOSFET models with 0.18 µm and 0.35 µm CMOS technology have been used to simulate this circuit. The simulation results of this work are presented and compared with previous works reported in the literature. The experimental simulation results obtained by the CS algorithm satisfy all desired specifications for this circuit.

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