scholarly journals Mechanisms of Multidrug Resistance in Cancer Chemotherapy

2020 ◽  
Vol 21 (9) ◽  
pp. 3233 ◽  
Author(s):  
Karol Bukowski ◽  
Mateusz Kciuk ◽  
Renata Kontek
Keyword(s):  
Multidrug Resistance ◽  
Cancer Treatment ◽  
Anticancer Agents ◽  
Alkylating Agents ◽  
Gene Mutations ◽  
Resistance Mechanisms ◽  
Chemotherapeutic Agents ◽  
Future Research ◽  
Repair Capacity ◽  
Dna Repair Capacity

Cancer is one of the main causes of death worldwide. Despite the significant development of methods of cancer healing during the past decades, chemotherapy still remains the main method for cancer treatment. Depending on the mechanism of action, commonly used chemotherapeutic agents can be divided into several classes (antimetabolites, alkylating agents, mitotic spindle inhibitors, topoisomerase inhibitors, and others). Multidrug resistance (MDR) is responsible for over 90% of deaths in cancer patients receiving traditional chemotherapeutics or novel targeted drugs. The mechanisms of MDR include elevated metabolism of xenobiotics, enhanced efflux of drugs, growth factors, increased DNA repair capacity, and genetic factors (gene mutations, amplifications, and epigenetic alterations). Rapidly increasing numbers of biomedical studies are focused on designing chemotherapeutics that are able to evade or reverse MDR. The aim of this review is not only to demonstrate the latest data on the mechanisms of cellular resistance to anticancer agents currently used in clinical treatment but also to present the mechanisms of action of novel potential antitumor drugs which have been designed to overcome these resistance mechanisms. Better understanding of the mechanisms of MDR and targets of novel chemotherapy agents should provide guidance for future research concerning new effective strategies in cancer treatment.

Down-regulation of DNA repair in human CD34+progenitor cells corresponds to increased drug sensitivity and apoptotic response

Blood ◽  
2002 ◽  
Vol 100 (3) ◽  
pp. 845-853 ◽  
Author(s):  
Claudia Buschfort-Papewalis ◽  
Thomas Moritz ◽  
Bernd Liedert ◽  
Jürgen Thomale
Keyword(s):  
Dna Repair ◽  
Comet Assay ◽  
Alkylating Agents ◽  
Reaction Products ◽  
Repair Capacity ◽  
Dna Repair Capacity ◽  
Repair Processes ◽  
Human Cd34 ◽  
Cd34 Cells ◽  
Cell Fractions

Abstract Although DNA repair processes have been shown to considerably modulate the cytotoxic effects of alkylating agents, little information is available on the role of these mechanisms in chemotherapy-induced myelosuppression. Therefore, we have analyzed in detail the DNA repair capacity of primary human hematopoietic cells from cord blood (CB) or bone marrow (BM) by 2 functional assays, the immunocytologic assay (ICA) and single-cell gel electrophoresis (comet assay). Besides substantial interindividual differences, we consistently observed significantly lower repair capacity of CD34+ cells in comparison to CD34−, CD19+, or CD33+ cells of the same donor. After exposure to the alkylating agent ethylnitrosourea (EtNU), the comet assay displayed on average twice as many DNA single-strand breaks (SSBs) in CD34+ cells and a tripled half-life of these lesions in comparison to corresponding CD34− cells. Similarly, reduced SSB repair activity in CD34+ cells was detected following melphalan or cisplatin application. When specific antibodies were used to monitor DNA reaction products of these drugs, adduct levels were significantly higher and lesions persisted longer in the CD34+ fraction. To assess the contribution of individual pathways to overall DNA repair, modulators blocking defined steps in repair processes were coapplied with alkylating drugs. Similar “modulation pattern” in corresponding CD34+ and CD34− cell fractions indicated a generalized reduction in DNA repair capacity of CD34+ cells, rather than deficiencies in a specific pathway. Because CD34+ cells also displayed higher frequencies of apoptosis in response to melphalan or cisplatin, these findings may help to explain the myelosuppression after exposure to alkylating agents.

scholarly journals Targeted Nanostructured Lipid Carrier Containing Galangin as a Promising Adjuvant for Improving Anticancer Effects of Chemotherapeutic Agents

2021 ◽  
Author(s):  
Hamed Hajipour ◽  
Mohammad Nouri ◽  
Marjan Ghorbani ◽  
Ali Bahramifar ◽  
Reza Zolfaghari Emameh ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Anticancer Agents ◽  
System Size ◽  
Homogenization Method ◽  
Chemotherapeutic Agents ◽  
Nanostructured Lipid Carrier ◽  
Anticancer Effects ◽  
Anti Cancer ◽  
Abc Transporter Genes ◽  
Apoptotic Effects

Abstract Purpose Resistance to chemotherapeutic drugs is the main limitation of cancer therapy. The combination use of anticancer agents and Galangin (a naturally active flavonoid) amplifies the effectiveness of cancer treatment. This study aimed to prepare Arginyl-glycyl-aspartic acid (RGD) containing nanostructured lipid carrier (NLC-RGD) to improve the bioavailability of Galangin and explore its ability in improving the anti-cancer effects of doxorubicin (DOX). Methods Galangin loaded-NLC-RGD was prepared by hot homogenization method and characterized by diverse techniques. Then, cytotoxicity, uptake, and apoptosis induction potential of prepared nanoparticles beside the DOX were evaluated. Finally, the expression level of some ABC transporter genes was evaluated in Galangin loaded-NLC-RGD treated cells. Results Nanoparticles with appropriate characteristics of the delivery system (size: 120 nm, PDI: 0.23, spherical morphology, and loading capacity: 59.3 mg/g) were prepared. Uptake experiments revealed that NLC-RGD promotes the accumulation of Galangin into cancerous cells by integrin-mediated endocytosis. Results also showed higher cytotoxicity and apoptotic effects of DOX + Galangin loaded-NLC-RGD in comparison to DOX + Galangin. Gene expression analysis demonstrated that Galangin loaded-NLC-RGD downregulates ABCB1, ABCC1, and ABCC2 more efficiently than Galangin. Conclusion These findings indicated that delivery of Galangin by NLC-RGD makes it an effective adjuvant to increase the efficacy of chemotherapeutic agents in cancer treatment.

scholarly journals CRISPR-dCas9-Based Artificial Transcription Factors to Improve Efficacy of Cancer Treatment With Drug Repurposing: Proposal for Future Research

2021 ◽  
Vol 10 ◽  
Author(s):  
Alejandro Martinez-Escobar ◽  
Benjamín Luna-Callejas ◽  
Eva Ramón-Gallegos
Keyword(s):  
Transcription Factors ◽  
Cancer Treatment ◽  
Drug Repurposing ◽  
Resistance Mechanisms ◽  
Cancer Drug ◽  
Future Research ◽  
Cancer Therapies ◽  
Advantages And Disadvantages ◽  
Artificial Transcription Factors ◽  
Repurposed Drugs

Due to the high resistance that cancer has shown to conventional therapies, it is difficult to treat this disease, particularly in advanced stages. In recent decades, treatments have been improved, being more specific according to the characteristics of the tumor, becoming more effective, less toxic, and invasive. Cancer can be treated by the combination of surgery, radiation therapy, and/or drug administration, but therapies based on anticancer drugs are the main cancer treatment. Cancer drug development requires long-time preclinical and clinical studies and is not cost-effective. Drug repurposing is an alternative for cancer therapies development since it is faster, safer, easier, cheaper, and repurposed drugs do not have serious side effects. However, cancer is a complex, heterogeneous, and highly dynamic disease with multiple evolving molecular constituents. This tumor heterogeneity causes several resistance mechanisms in cancer therapies, mainly the target mutation. The CRISPR-dCas9-based artificial transcription factors (ATFs) could be used in cancer therapy due to their possibility to manipulate DNA to modify target genes, activate tumor suppressor genes, silence oncogenes, and tumor resistance mechanisms for targeted therapy. In addition, drug repurposing combined with the use of CRISPR-dCas9-based ATFs could be an alternative cancer treatment to reduce cancer mortality. The aim of this review is to describe the potential of the repurposed drugs combined with CRISPR-dCas9-based ATFs to improve the efficacy of cancer treatment, discussing the possible advantages and disadvantages.

scholarly journals Utilizing Melatonin to Alleviate Side Effects of Chemotherapy: A Potentially Good Partner for Treating Cancer with Ageing

2020 ◽  
Vol 2020 ◽  
pp. 1-20
Author(s):  
Zhiqiang Ma ◽  
Liqun Xu ◽  
Dong Liu ◽  
Xiaoyan Zhang ◽  
Shouyin Di ◽  
...  
Keyword(s):  
Side Effects ◽  
Alkylating Agents ◽  
Protective Role ◽  
Chemotherapeutic Agents ◽  
Future Research ◽  
Drug Induced ◽  
Protective Actions ◽  
Age Related ◽  
Comprehensive Reference

Persistent senescence seems to exert detrimental effects fostering ageing and age-related disorders, such as cancer. Chemotherapy is one of the most valuable treatments for cancer, but its clinical application is limited due to adverse side effects. Melatonin is a potent antioxidant and antiageing molecule, is nontoxic, and enhances the efficacy and reduces the side effects of chemotherapy. In this review, we first summarize the mitochondrial protective role of melatonin in the context of chemotherapeutic drug-induced toxicity. Thereafter, we tabulate the protective actions of melatonin against ageing and the harmful roles induced by chemotherapy and chemotherapeutic agents, including anthracyclines, alkylating agents, platinum, antimetabolites, mitotic inhibitors, and molecular-targeted agents. Finally, we discuss several novel directions for future research in this area. The information compiled in this review will provide a comprehensive reference for the protective activities of melatonin in the context of chemotherapy drug-induced toxicity and will contribute to the design of future studies and increase the potential of melatonin as a therapeutic agent.

scholarly journals Multidrug resistance in tumour cells: characterisation of the multidrug resistant cell line K562-Lucena 1

2001 ◽  
Vol 73 (1) ◽  
pp. 57-69 ◽  
Author(s):  
VIVIAN M. RUMJANEK ◽  
GILMA S. TRINDADE ◽  
KAREN WAGNER-SOUZA ◽  
MICHELE C. MELETTI-DE-OLIVEIRA ◽  
LUIS F. MARQUES-SANTOS ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cell Line ◽  
Anticancer Agents ◽  
Vinca Alkaloid ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Resistant Cell ◽  
Cross Reactivity ◽  
Resistant Cell Line ◽  
P Glycoprotein

Multidrug resistance to chemotherapy is a major obstacle in the treatment of cancer patients. The best characterised mechanism responsible for multidrug resistance involves the expression of the MDR-1 gene product, P-glycoprotein. However, the resistance process is multifactorial. Studies of multidrug resistance mechanisms have relied on the analysis of cancer cell lines that have been selected and present cross-reactivity to a broad range of anticancer agents. This work characterises a multidrug resistant cell line, originally selected for resistance to the Vinca alkaloid vincristine and derived from the human erythroleukaemia cell K562. This cell line, named Lucena 1, overexpresses P-glycoprotein and have its resistance reversed by the chemosensitisers verapamil, trifluoperazine and cyclosporins A, D and G. Furthermore, we demonstrated that methylene blue was capable of partially reversing the resistance in this cell line. On the contrary, the use of 5-fluorouracil increased the resistance of Lucena 1. In addition to chemotherapics, Lucena 1 cells were resistant to ultraviolet A radiation and hydrogen peroxide and failed to mobilise intracellular calcium when thapsigargin was used. Changes in the cytoskeleton of this cell line were also observed.

scholarly journals Nanoparticles for Cancer Therapy: Current Progress and Challenges

2021 ◽  
Author(s):  
Shreelaxmi Gavas ◽  
Sameer Quazi ◽  
Tomasz Karpiński
Keyword(s):  
Multidrug Resistance ◽  
Cancer Treatment ◽  
Resistance Mechanisms ◽  
Multi Drug Resistance ◽  
Cancer Therapies ◽  
Therapeutic Implications ◽  
Current Perspective ◽  
Reduced Toxicity

Cancer is one of the leading causes of death and morbidity with a complex pathophysiology. Traditional cancer therapies include chemotherapy, radiation therapy, targeted therapy, and immunotherapy. However, limitations such as lack of specificity, cytotoxicity, and multi-drug resistance pose a substantial challenge for favorable cancer treatment. The advent of nanotechnology has revolutionized the arena of cancer diagnosis and treatment. Nanoparticles (1-100nm) can be used in the treatment of cancer owing to their specific advantages such as biocompatibility, reduced toxicity, more excellent stability, enhanced permeability and retention effect, and precise targeting. Nanoparticles are classified into several main categories. The nanoparticle drug delivery system is particular and utilizes tumor and tumor environment characteristics. Nanoparticles not only solve the limitations of conventional cancer treatment but also overcome multidrug resistance. Additionally, as new multidrug resistance mechanisms are unraveled and studied, nanoparticles are being investigated more vigorously. Various therapeutic implications of nano-formulations have created brand new perspectives for cancer treatment. However, a majority of the research is limited to in vivo and in vitro studies, and the number of nano-drugs that are approved has not much amplified over the years. In this review, we discuss numerous types of nanoparticles, targeting mechanisms along with approved nanotherapeutics for oncological implications in cancer treatment. Further, we also summarize the current perspective, advantages, and challenges in clinical translation.

scholarly journals Nanoparticles for Cancer Therapy: Current Progress and Challenges

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Shreelaxmi Gavas ◽  
Sameer Quazi ◽  
Tomasz M. Karpiński
Keyword(s):  
Multidrug Resistance ◽  
Cancer Treatment ◽  
Resistance Mechanisms ◽  
Multi Drug Resistance ◽  
Cancer Therapies ◽  
Therapeutic Implications ◽  
Current Perspective ◽  
Reduced Toxicity

AbstractCancer is one of the leading causes of death and morbidity with a complex pathophysiology. Traditional cancer therapies include chemotherapy, radiation therapy, targeted therapy, and immunotherapy. However, limitations such as lack of specificity, cytotoxicity, and multi-drug resistance pose a substantial challenge for favorable cancer treatment. The advent of nanotechnology has revolutionized the arena of cancer diagnosis and treatment. Nanoparticles (1–100 nm) can be used to treat cancer due to their specific advantages such as biocompatibility, reduced toxicity, more excellent stability, enhanced permeability and retention effect, and precise targeting. Nanoparticles are classified into several main categories. The nanoparticle drug delivery system is particular and utilizes tumor and tumor environment characteristics. Nanoparticles not only solve the limitations of conventional cancer treatment but also overcome multidrug resistance. Additionally, as new multidrug resistance mechanisms are unraveled and studied, nanoparticles are being investigated more vigorously. Various therapeutic implications of nanoformulations have created brand new perspectives for cancer treatment. However, most of the research is limited to in vivo and in vitro studies, and the number of approved nanodrugs has not much amplified over the years. This review discusses numerous types of nanoparticles, targeting mechanisms, and approved nanotherapeutics for oncological implications in cancer treatment. Further, we also summarize the current perspective, advantages, and challenges in clinical translation.

Research Progress in Flavonoids as Potential Anticancer Drug Including Synergy with Other Approaches

2020 ◽  
Vol 20 (20) ◽  
pp. 1791-1809 ◽  
Author(s):  
Yusuf Hussain ◽  
Suaib Luqman ◽  
Abha Meena
Keyword(s):  
Multidrug Resistance ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cell Signalling ◽  
Resistance Mechanisms ◽  
Research Progress ◽  
Potential Candidate ◽  
Proliferating Cells ◽  
Oncology Research

Background: In chemotherapy for cancer, conventional drugs aim to target the rapidly growing and dividing cells at the early stages. However, at an advanced stage, cancer cells become less susceptible because of the multidrug resistance and the recruitment of alternative salvage pathways for their survival. Besides, owing to target non-selectivity, healthy proliferating cells also become vulnerable to the damage. The combination therapies offered using flavonoids to cure cancer not only exert an additive effect against cancer cells by targetting supplementary cell carnage pathways but also hampers the drug resistance mechanisms. Thus, the review aims to discuss the potential and pharmacokinetic limitations of flavonoids in cancer treatment. Further successful synergistic studies reported using flavonoids to treat cancer has been described along with potential drug delivery systems. Methods: A literature search was done by exploring various online databases like Pubmed, Scopus, and Google Scholar with the specific keywords like “Anticancer drugs”, “flavonoids”, “oncology research”, and “pharmacokinetics”. Results: Dietary phytochemicals, mainly flavonoids, hinder cell signalling responsible for multidrug resistance and cancer progression, primarily targeting cancer cells sparing normal cells. Such properties establish flavonoids as a potential candidate for synergistic therapy. However, due to low absorption and high metabolism rates, the bioavailability of flavonoids becomes a challenge. Such challenges may be overcome using novel approaches like derivatization, and single or co-delivery nano-complexes of flavonoids with conventional drugs. These new approaches may improve the pharmacokinetic and pharmacodynamic of flavonoids. Conclusion: This review highlights the application of flavonoids as a potential anticancer phytochemical class in combination with known anti-cancer drugs/nanoparticles. It also discusses flavonoid’s pharmacokinetics and pharmacodynamics issues and ways to overcome such issues. Moreover, it covers successful methodologies employed to establish flavonoids as a safe and effective phytochemical class for cancer treatment.

Overcome Multidrug Resistance in Colorectal Cancer by Natural Compounds

2020 ◽  
Vol 12 (7) ◽  
pp. 933-949
Author(s):  
Yanxi Li ◽  
Zhexian Liu ◽  
Xingqi Guo ◽  
Siping Ma
Keyword(s):  
Colorectal Cancer ◽  
Multidrug Resistance ◽  
Cancer Treatment ◽  
Natural Compounds ◽  
Chemotherapeutic Agents ◽  
Chemotherapeutic Drugs ◽  
Postoperative Adjuvant Chemotherapy ◽  
Traditional Treatment ◽  
Chemopreventive Agents ◽  
Colorectal Cancer Treatment

Colorectal cancer, a commonly diagnosed cancer, is a leading cause of cancer-associated deaths in men and women globally. Amongst the current treatments for colorectal cancer including radiotherapy and chemotherapy, surgical resection provides the most benefit. However, the recurrence rate after traditional treatment is high, and treatment failure is related to recurrence and metastasis. Although postoperative adjuvant chemotherapy can reduce these factors to prolong patient life, systemic toxicity and resistance to chemotherapeutic drugs reduces their effectiveness for colorectal cancer treatment. Therefore, multidrug resistance is a major cause for concern in colorectal cancer treatment. This review focuses on recent studies of natural compounds derived from plants, animals or marine organisms related to colorectal cancer treatment including published clinical trials. Studies have indicated that natural compounds might be of benefit as chemotherapeutic agents, chemopreventive agents, or chemosensitizers in combination chemotherapy strategies. We discuss the mechanisms involved in the reversal of multidrug resistance by natural products for cancer chemotherapy. The evidence suggests natural compounds might have potential for the prevention and treatment of colorectal cancer.

Selective Cytotoxic Effects of 5-Trifluoromethoxy-1H-indole-2,3-dione 3-Thiosemicarbazone Derivatives on Lymphoid-originated Cells

2021 ◽  
Vol 21 ◽  
Author(s):  
Ferdane Danışman-Kalındemirtaş ◽  
Serap Erdem-Kuruca ◽  
Kadriye Akgün-Dar ◽  
Zeynep Karakaş ◽  
Özge Soylu ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Cell Lines ◽  
Anticancer Agents ◽  
K562 Cell ◽  
Chemotherapeutic Agents ◽  
New Drugs ◽  
Myelogenous Leukemia ◽  
Lymphoma Cells ◽  
Cytotoxic Effects ◽  
Compound C

Aim: The present study aims to identify the anticancer effect of novel 1H-indole-2,3-dione 3-thiosemicarbazone derivatives. These compounds could be promissing anticancer agents in leukemia treatment. Background : Conventional chemotherapeutic agents accumulate in both normal and tumor cells due to non-specificity. For effective cancer treatment, new drugs need to be developed to make chemotherapeutics selective for cancer cells. The ultimate goal of cancer treatment is to reduce systemic toxicity and improve the quality of life. Method: In this study, the anticancer effects of 5-trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazone derivatives (A-L) were investigated in chronic myelogenous leukemia K562, Burkitt’s lymphoma P3HR1, acute promyelocytic leukemia HL60 cells and vincristine-resistant sublines of K562 and P3HR1 cells. Additionally, the compounds were tested on lymphoid derived cells from ALL patients. In order to investigate the particular mechanism of death caused by the cytotoxic effects of the compounds, immunohistochemical caspase 3 staining was performed in P3HR1 cells, and resulting apoptotic activities were demonstrated. Result: All compounds tested have been found to have cytotoxic effects against lymphoma cells at submicromolar concentrations (IC50= 0.89-1.80 µM). Most compounds show significant selectivity for the P3HR1 and P3HR1 Vin resistant. The most effective and selective compound is 4-bromophenyl substituted compound I (IC50=0.96 and 0.89 µM). Cyclohexyl and benzyl substituted compounds D and E have also been found to have cytotoxic effects against K562 cell lines (IC50=2.38 µM), while the allyl substituted compound C is effective on all cell lines (IC50=1.13-2.21 µM). 4-Fluorophenyl substituted F compound has been observed to be effective on all cells (IC50=1.00-2.41 µM) except K562 cell. Compound C is the only compound that shows inhibition of HL-60 cells (IC50= 1.13 µM). Additionally, all compounds exhibited cytotoxic effects on lymphoid-derived cells at 1µM concentration. These results are in accordance with the results obtained in lymphoma cells. Conclusion: All compounds tested have submicromolar concentrations of cytotoxic effects on cells. These compounds hold promise for the future treatment of leukemia cancer.

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