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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
MULTI-DRUG RESISTANCE IN CANCER The book details the mechanisms underlying multi-drug cellular resistance and the targets of novel chemotherapeutic agents. Cancer is a major killer all over the world. Even with all the progress made, chemotherapy is still the mainstay of modern cancer treatment. The progression of the cellular defeat of numerous independent anticancer drugs in terms of their chemical structure is a major barrier to successful chemotherapy. Multi-drug resistance (MDR) is a term for the fact that most cancer patients exhibit this phenomenon. According to the numbers, drug resistance carries the blame for 90% of cancer patient deaths. Refractory cancer and tumor recurrence are common outcomes of prolonged chemotherapy. Because of the prevalence of drug-resistance mutations, the difficulty of treating tumors increases and the therapeutic efficacy of drugs decreases. Multi-Drug Resistance in Cancer: Mechanism and Treatment Strategies contains nine chapters that cover topics such as: studying the mechanics of resistance to drugs by autophagy; studies to delineate the role of efflux transporters; expression of drug transporters; resistance to targeted therapies in breast cancer; advances in metallodrug driven combination treatment for cancer; and use of natural agents for the overcoming of cancer drug resistance. The book aims to provide the latest data on the mechanisms of cellular resistance to anticancer agents currently used in clinical treatment. It provides a better understanding of the mechanisms of MDR and targets of novel chemotherapy agents which should guide future research concerning new effective strategies in cancer treatment. Audience This book is written for pharmaceutical and biomedical scientists and researchers at both the bench and in the clinic who are interested in the mechanisms and strategies for overcoming cancer's multi-drug resistance.
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Veröffentlichungsjahr: 2023
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Table of Contents
Cover
Series Page
Title Page
Copyright Page
Dedication Page
Foreword
Preface
Acknowledgment
1 Multi-Drug Resistance in Cancer: Understanding of Treatment Strategies
1.1 Introduction
1.2 Both Congenital and Developed Resistance to Drugs
1.3 Drug-Resistance Mechanisms
1.4 Senescence Escape
1.5 Epigenetic Alterations
1.6 Tumor Heterogeneity
1.7 Tumor Microenvironment
1.8 Epithelial to Mesenchymal Transition
1.9 Conclusion
References
2 Understanding Different Mechanisms Involved in Cancer Drug Resistance: Proposing Novel Strategies to Overcome MDR
2.1 Introduction
2.2 Drug Resistance: Internal and External Variables
2.3 Improving the Pharmacokinetics
2.4 Changing the Aim of the Chemotherapy Agents
2.5 Improving the DNA Repair Process
2.6 MicroRNA in Cancer Drug Resistance
2.7 Conclusion
References
3 Molecular Mechanism of Multi-Drug Resistant Cancer Cells
3.1 Introduction
3.2 Types of Drug Resistance
3.3 Mechanisms of Drug Resistance
3.4 Reduction in Drug Activity and Cellular Absorption
3.5 Instability in the Genome and Medication Resistance
3.6 RNA Interference Therapy
3.7 Methods of Physical Intervention to Treat MDR
3.8 Conclusion
References
4 Natural Products for Clinical Management of Drug Resistant Cancer Cells
4.1 Introduction
4.2 Resistance Mechanisms
4.3 Antitumor Plants for Multi-Drug-Resistant Cells
4.4 Qualea Species and Their Medical Applications
4.5 Antitumor Activity of Qualea Grandiflora and Qualea Multiflora
4.6 Conclusion
References
5 Understanding of Autophagy to Combat MDR During Anticancer Therapy
5.1 Introduction
5.2 Mechanisms of Autophagy
5.3 Mechanisms of MDR
5.4 Correlation Between Autophagy and Multi-Drug Resistance
5.5 The Cytoprotective Effect of Autophagy in the Regulation of Multi-Drug Resistance
5.6 Increased Autophagy Facilitates Multi-Drug Resistance
5.7 Autophagy Inhibition Improves Chemotherapy in MDR Cancers
5.8 Overcoming MDR With Autophagic Cell Death
5.9 Autophagy Kills Apoptosis-Deficient MDR Cancer Cells
5.10 Autophagy Promotes Chemosensitivity
5.11 Conclusion
References
6 Transporter Inhibitors: A Chemotherapeutic Regimen to Improve the Clinical Outcome of Colorectal Cancer
6.1 Introduction
6.2 CRC Transporters or ATP-Binding Cassette
6.3 Clinical Evidence for the Function of ABC Transporters in CRC MDR
6.4 General Approaches
6.5 By Blocking Tyrosine Kinase Inhibitors from Inhibiting MDR Transporters
6.6 Components Produced from Natural Sources that Inhibit MDR Transporters
6.7 Inhibiting ABC Transporters in Other Ways for CRC MDR Circumvention
6.8 Challenges and Future Prospective
6.9 Conclusion
References
7 Epithelial to Mesenchymal Transition (EMT): Major Contribution to Cancer Drug Therapy Resistance
7.1 Introduction
7.2 EMT and Tumor Resistance:
In Vitro, In Vivo,
and Clinical Trials
7.3 Tumor Microenvironment Regulates EMT
7.4 Drug Resistance and EMT Bioinformatics
7.5 Conclusion
References
8 Advances in Metallodrug-Driven Combination Therapy for Treatment of Cancer
8.1 Introduction
8.2 Cancer Treatment Using Combination Therapy
8.3 Combined Treatment with Metallodrugs for Cancer Treatment
8.4 Nonplatinum Metallodrugs
8.5 Conclusion
References
9 Novel Strategies Preventing Emergence of MDR in Breast Cancer
9.1 Introduction
9.2 Breast Cancer Categorization and Epidemiological Studies
9.3 Multi-Drug Resistance in Breast Cancer
9.4 Drug Efflux Transporters in Breast Cancer
9.5 Excessive Synthesis or Overexpression of Transporters for the Expulsion of Drugs
9.6 Nanotherapeutic Approach for MDR Reversal
9.7 Breast Cancer’s MDR Cure Problems and Future Outlook
9.8 Conclusion
References
Index
End User License Agreement
List of Tables
Chapter 2
Table 2.1 Inhibition of disease and drug-resistant processes and pathways.
Chapter 5
Table 5.1 Recent studies on the pro-survival role of autophagy in multi-drug-r...
Chapter 6
Table 6.1 Clinical trials showing potential chemotherapeutic medicines antican...
List of Illustrations
Chapter 1
Figure 1.1 Diagrammatic representation of cancerous cells developing resistanc...
Figure 1.2 Diagrammatic representation of the heterogenous origin of CAFs and ...
Chapter 2
Figure 2.1 The drug release mechanism via the ABC channel outside the cell.
Figure 2.2 Schematic diagram of the mechanism of inhibition of the cell death.
Chapter 3
Figure 3.1 Molecular and cellular mechanisms leading to cancer medication resi...
Figure 3.2 Schematic representation of the structural organization of ABCB1, A...
Figure 3.3 Cancer-related genes ABCB1, ABCC1, and ABCG2 interact with one anot...
Chapter 4
Figure 4.1 Diagrammatic representation of natural products in cancer therapy.
Chapter 5
Figure 5.1 Schematic representation of cancerous autophagy and the development...
Figure 5.2 Schematic representation of the mechanism of MDR.
Figure 5.3 Representation of mechanism of action of autophagy inhibition impro...
Figure 5.4 When autophagy is activated, drug-resistant cancer cells become mor...
Chapter 6
Figure 6.1 A diagram showing how ABCG2 overexpression contributes to MDR and h...
Chapter 7
Figure 7.1 Schematic representation of EMT and tumor resistance.
Figure 7.2 Potential therapeutic target for reversing treatment resistance: th...
Chapter 8
Figure 8.1 Chemical structure of cisplatin complex.
Chapter 9
Figure 9.1 Schematic representation of the variety of methods to combat the mu...
Guide
Cover Page
Series Page
Title Page
Copyright Page
Dedication Page
Foreword
Preface
Acknowledgment
Table of Contents
Begin Reading
Index
WILEY END USER LICENSE AGREEMENT
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Scrivener Publishing100 Cummings Center, Suite 541JBeverly, MA 01915-6106
Publishers at ScrivenerMartin Scrivener ([email protected])Phillip Carmical ([email protected])
Multi-Drug Resistance in Cancer
Mechanism and Treatment Strategies
Rishabha Malviya, Arun Kumar Singh and Deepika Yadav
Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, India
This edition first published 2023 by John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA and Scrivener Publishing LLC, 100 Cummings Center, Suite 541J, Beverly, MA 01915, USA© 2023 Scrivener Publishing LLCFor more information about Scrivener publications please visit www.scrivenerpublishing.com.
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Library of Congress Cataloging-in-Publication Data
ISBN 978-1-394-20921-7
Cover image: Pixabay.comCover design by Russell Richardson
This book is dedicated to all healthcare professionals.Our love for the profession shall live forever.
Foreword
Dr. Rishabha Malviya is known to me through his research and publications. I am glad to write the Foreword for this book. This is an excellent book on one of the topics which is directly related to the health of people in all countries. The title of the book is self-explanatory “Multi-Drug Resistance in Cancer: Mechanism and Treatment Strategies”. One of the most common ways to treat cancer is with chemotherapy, but this approach is severely hampered by multi-drug resistance, which occurs when cancer cells develop resistance to a wide variety of drugs with different structures and mechanisms of action. This book examines the underlying biology of cancer drug resistance and offers fresh approaches for combating the problem. Many pathways by which cancer cells acquire the ability to resist multiple drugs have been identified over the past three decades. In addition, the development of agents or strategies to overcome resistance has been the subject of intense study. Overexpression of ATP binding cassette drug transporters like P-glycoprotein, multi-drug resistance proteins (MRPs), and breast cancer resistance proteins are just some of the topics covered in this book, along with drug ratio dependent antagonism and the paradigm of cancer stem cells. A variety of methods, such as the creation of compounds that block drug transporter function and the regulation of transporter expression, are outlined in the book as means of overcoming multi-drug resistance. Methods for studying drug resistance in animal models, techniques for detecting and imaging drug transporters, and approaches for gauging the effectiveness of resistance reversal agents can all be found within the covers of this book. This book is written for researchers at both the bench and in the clinic who are interested in the mechanisms and strategies for overcoming cancer’s multi-drug resistance. The technical depth and information in this book will, in my belief, be helpful for healthcare professionals in preventing the emergence of multi-drug resistance in cancer therapy.
Prof. (Dr.) Kamla Pathak
Dean, Faculty of Pharmacy
Uttar Pradesh University of Medical Sciences,
Saifai, Etawah,
Uttar Pradesh, India
Preface
Cancer is a major killer all over the world. Even with all the progress made, chemotherapy is the mainstay of modern cancer treatment and still the gold standard. The progression of cellular defeat of numerous independent anticancer drugs in terms of their chemical structure is a major barrier to successful chemotherapy. Multi-drug resistance (MDR) is a term for the fact that most cancer patients exhibit this phenomenon. According to the numbers, drug resistance carries the blame for ninety percent of cancer patient deaths. Refractory cancer and tumour recurrence are common outcomes of prolonged chemotherapy Because of the prevalence of drug-resistance mutations, the difficulty of treating tumours increases and the therapeutic efficacy of drugs decreases.
This book covers a wide range of topics related to multi-drug resistance, from drug ratio-dependent antagonism and cancer stem cells to overexpression of ATP-binding cassette drug carrier like P-glycoprotein, multi-drug resistant proteins and breast cancer resistant proteins. Multi-drug resistance can be overcome by developing elements which resist drug carrier activity or modulating transporter expression. This book is an effort to keep the reader abreast of the most recent findings regarding the methods of cellular defence to current agents that fight against cancer. It should help direct future research toward the discovery of more efficient approaches to cancer treatment by elucidating the methods of MDR and the intended recipients of novel chemotherapeutic agents.
MDR in Cancer: Mechanism & Treatment Strategies, has 9 chapters on topics such as, autophagy and drug resistance, efflux transporters, drug transporter expression, breast cancer resistance to targeted therapies, advances in metallodrug-driven combination cancer treatment, and using natural agents to overcome cancer tolerance to drugs. Chapter 1 outlines treatment strategies for MDR in cancer. In Chapter 2, the various methods that contribute to cancer tolerance to drugs and the novel strategies to overcome multi-drug resistance are described. The molecular systems for the treatment of drug addiction-resistant cancer cells and natural products for the clinical management of drug resistance in these cells are the primary topics of discussion in Chapters 3 and 4, respectively. Defeating multi-drug resistance (MDR) through autophagy and using transport inhibitors to better the clinical outcome of colorectal cancer are topics covered in the next two chapters. Substantial contributions of epithelial-mesenchymal transitions to resistance to cancer drug therapy are discussed in Chapter 7. The evolution of metal-based drugs is covered in detail in Chapter 8, and the book concludes with a final chapter presenting a number of novel approaches for halting the emergence of multi-drug resistance in breast cancer. This book is written for researchers at both the bench and in the clinic who are interested in the mechanisms and strategies for overcoming cancer’s multi-drug resistance.
The Authors
May 2023
Acknowledgment
When I started working on book writing, the first topic that came to mind was cancer, but I was afraid because it was a challenging task. But now that I have finally worked on the subject, I find it has been a very pleasant experience. It is, by far, more rewarding and motivating than what I had imagined. At the outset, I would like to begin by expressing our gratitude to the Almighty, whose unending blessing and supreme power enable us to accomplish all of our goals.
Although this phase in my life was full of ups and downs, I will always be thankful to my family for their unwavering support and encouragement, which allowed me to accomplish this work.
I want to express my gratitude to the management of Galgotias University for motivating me for research and recognizing my potential, and for inspiring me every day.
I would like to express my deepest gratitude to Miss. Sonali Sundram, Faculty, Department of Pharmacy, Galgotias University, India for her continuous motivation and support. Her enthusiasm for hard work and dedication toward work always inspires me.
Many thanks to my students (undergraduate and postgraduate), colleagues and all the co-authors for being part of this book, because without their participation, the writing of this book would not have been completed.
Lastly, I would like to thank our publisher for their support, innovative suggestions, and guidance in bringing out this edition.
Rishabha Malviya
May 2023
1Multi-Drug Resistance in Cancer: Understanding of Treatment Strategies
Rishabha Malviya*, Arun Kumar Singh and Deepika Yadav
Abstract
In the United States, cancer is the second largest killer. Surgery, cytotoxic chemotherapy, targeted therapy, radiation therapy, endocrine therapy, and immunotherapy are among the most important therapies for cancer management. Resistance to conventional chemotherapeutic agents and/or innovative targeted medications remains a significant challenge in cancer treatment despite decades of effort and progress. Cancer relapses are a leading cause of mortality, and they are often the result of either preexisting drug resistance (intrinsic) or the development of new drug resistance (acquired). Drug resistance is more difficult to manage due to the heterogeneity of people and tumors, as well as cancer’s adaptability in evading therapy. To better direct future cancer therapy and boost outcomes, a better understanding of the factors that contribute to drug resistance is required. In this synopsis, examination of both innate and acquired forms of resistance. In addition, new information about the mechanisms of drug resistance will be presented and discussed. The details of recent findings that highlight the role of ATP in drug resistance, including the presence of extremely high levels of extracellular ATP within tumors and the importation of extracellular ATP into tumor cells from the environment has been discussed here. Due to the complex nature of drug resistance, it is possible that combining and customizing treatments for cancer patients may be the most effective strategy for combating the disease.
Keywords: Cancer, drug resistance, heterogeneity of tumor, combination therapy, acquired resistance
1.1 Introduction
To put it simply, cancer is the second largest killer in the United States [1]. A total of 1.7 million persons were diagnosed with cancer in 2017, with 0.6 million succumbing to the disease [2]. Up to 90% of cancer-related fatalities are caused by medication resistance and the ensuing ineffectiveness of treatment [3–7]. The mechanism of drug resistance against cancerous cells is illustrated in Figure 1.1.
Cancer cells that have acquired tolerance to pharmacological therapy are said to have developed drug resistance. Many different physiological and molecular pathways, including mutations and epigenetic alterations in cancer cells, upregulation of a previously conserved drug efflux pump, and others, contribute to the development of resistance to anticancer treatments.
Surgical resection, cytotoxic chemotherapy, targeted therapy, radiotherapy, irradiation, hormone therapy, and immunotherapy are now the cornerstones of cancer management [8–12]. Although there have been great strides achieved in cancer treatment over the last several decades, relapses a leading cause of cancer deaths are still often the result of the body’s resistance to chemotherapy or targeted medications. Many traditional chemotherapeutic anticancer medicines work by directly altering the DNA of cancer cells to destroy them. This method is inherently non-specific and may have severe side effects in certain patients. Many new medications that specifically target or inhibit cancer-promoting alterations have been produced in the last few decades. While the earliest stages of therapy with these medications may have spectacular outcomes, the vast majority of patients will eventually develop resistance. To provide just one example, between 30% and 55% of individuals with non-small cell lung cancer (NSCLC) have a recurrence and ultimately succumb to the disease [13]. Recurrence of ovarian adenocarcinoma is common, occurring in 50% to 70% of cases within a year following surgery and chemotherapy [14]. About 20 % of juvenile acute lymphoblastic leukemia patients suffer recurrence [15].
Figure 1.1 Diagrammatic representation of cancerous cells developing resistance against the drug.
Better knowledge of the processes behind the formation of drug resistance is critically required and will help to develop innovative treatment options and lead to better clinical results. This chapter will explain what drug resistance is and how it may be acquired or developed, as well as highlight recent findings on the causes of drug resistance and address novel approaches to combating drug resistance and enhancing the effectiveness of anticancer drugs.
1.2 Both Congenital and Developed Resistance to Drugs
The development of drug resistance may be classified as either innate or acquired. About half of all cancer patients with drug resistance have intrinsic resistance, which occurs before medication treatment, and 50 % have acquired resistance, which is produced by therapy [16, 17].
1.2.1 Intrinsic Resistance
For medications to have less of an effect, they must overcome the patient’s natural resistance to them, which is known as “intrinsic resistance.” (1) Preexisting (inherent) genetic mutations in the majority of tumors lead to decreased responsiveness of cancer cells, such as triple-negative breast cancer cells, to both chemo and target drugs; (2) heterogeneity of tumors in which preexisting insensitive subpopulations, including cancer stem cells, will be selected upon drug treatment, resulting in a relapse in later stages of treatment; (3) activation of intrigue resistant pathways (such as anticancer drugs).
Preexisting genetic mutation(s) of genes involved in cancer cell proliferation and/or apoptosis may cause cancer cells to be intrinsically resistant to drugs. Overexpression of HER2 has been linked to a worse response to cisplatin in patients with gastric cancer [18]. Increased resistance to chemotherapy is achieved by a process called epithelial-mesenchymal transition (EMT), which is triggered by increased HER2 gene expression by upregulating the transcription factor Snail. It was also discovered that the survival rate of HER2/Snail double-positive patients was lower than that of single-positive or double-negative patients.
EMT, resistance to p53-induced apoptosis, and a self-renewal drive were all demonstrated to be mediated by the transcriptional repressors Snail and Slug [19]. These two processes provide radiation and chemotherapeutic resistance to cancer stem cells (CSCs). Resistant cells have also been demonstrated to have greater mesenchymal characteristics [20, 21]. These parallel alterations establish a connection between inherent drug resistance, EMT, and CSCs.
Relapse after chemotherapeutic therapy may also be caused by preexisting resistant subpopulations in malignancies. Increasing data indicate that intratumoral genetic variability in primary cancers exists prior to therapeutic intervention [22–24]. The majority of tumor cells are vulnerable to the medicine; therefore, patients would initially react to treatment. After pharmacological therapy, however, the resistant subclones would multiply and produce a relapse [25–27]. This inherent drug resistance is sometimes misunderstood as acquired resistance since the tumor would initially shrink during treatment, leading many to believe that the resistance was gained as a result of therapy. Cancer stem cells (CSCs) are a self-renewing and differentiating subset of tumor cells that contribute to tumor development [28]. Multiple cancer types, including leukemia [29], glioblastoma [30], and pancreatic cancer [31], have documented their involvement in chemotherapeutic treatment resistance. It is possible that medication resistance may only be mitigated by the use of a combination treatment that simultaneously eliminates CSCs and the bulk of the tumor.
Anticancer medications are no exception; activation of intrinsic mechanisms intended to defend against environmental contaminants might decrease their therapeutic effects. ATP binding cassette (ABC) transporter-mediated drug efflux [32] and the glutathione (GSH)/glutathione S-transferase system are examples of such defence systems that operate to either decrease drug accumulation in cells or detoxify drug-treated cancer cells, respectively [33].
1.2.2 Acquired Resistance
Slowly diminishing anticancer activity after pharmacological therapy is a hallmark of acquired resistance. Tumor microenvironmental (TME) alterations, mutations in therapeutic targets, and secondary oncogene activation are all potential causes of acquired resistance.
Tumors that have been reduced in size may regain growth capability if they develop resistance to treatment. Eight patients with acute myeloid leukemia had their genetic profiles examined using whole-genome sequencing before and after relapse [34]. Genome-wide analysis of primary and recurrent cancers revealed previously unknown alterations in genes. Furthermore, the data demonstrated an increase in transversion mutations in recurrent tumors, which may indicate that DNA damage in cancer cells produced by cytotoxic chemotherapeutic treatments enhanced the likelihood of the development of new mutations.
When mutations or changes in the expression levels of the genes-producing target proteins occur in cancer cells, the cells may become resistant to the therapeutic effects of the medications. As an example of a secondary mutation inside the target kinase, the threonine 315 to isoleucine (T315I) mutation in the BCR-ABL kinase domain is a case in point. Although the BCR-ABL tyrosine kinase inhibitor (TKI) imatinib is widely used to treat chronic myelogenous leukemia, between 20% and 30% of individuals develop resistance to the drug or relapse following treatment [35]. The resistance may be explained, in part, by a point mutation in the fusion tyrosine kinase protein, T315I, which prevents it from functioning properly [35–37]. By replacing threonine 315 with isoleucine, the drug’s effectiveness is greatly diminished because the ATP-binding site of BCR-ABL no longer forms a hydrogen bond with imatinib.
The dynamic variations in TME during therapy may potentially lead to the development of drug resistance. Tumor cells and their microenvironment engage in cross-talk throughout disease progression and resistance. The interaction involves exosomes secreted by both cancer and stromal cells. Cancer cells and tumor-associated macrophages (TAMs) in the TME rely on exosomes, which are generated by cancer cells and contain specific miRNAs, to interact with one another, according to the research [38]. Neuroblastoma (NBL) tumor cells secrete exosomic miR-21, which stimulates tumor-associated macrophages (TAMs) to generate exosomic miR-155, which then silences the TERF1 gene in NBL cells. Increased telomerase activity and tolerance to chemotherapy would arise from reduced expression of TERF1, a protein that inhibits telomerase. As a result, drug resistance may be facilitated by the exchanging of exosomal miRNAs between tumor cells and stromal cells in the TME.
While tumors develop and are treated, the innate and acquired resistance mechanisms discussed above might coexist. There may be significant differences between the underlying mechanisms of intrinsic drug resistance and those of acquired drug resistance. Also possible is a gradual increase in the organism’s innate resistance to drugs. The susceptibility of individual cancer cells to a certain treatment is determined beforehand by the extent to which those cells exhibit inherent drug resistance. It is important to rule out the possibility of medication resistance by conducting genomic and other biochemical tests before designing the treatment strategy. Adjustments to treatment plans are necessary when acquired medication resistance has emerged.
One goal of cancer medication therapy should be to halt tumor development without triggering acquired, or at least unmanageable, drug resistance. Acquired drug resistance is a serious problem that has to be addressed in any effective drug treatment approach.
1.3 Drug-Resistance Mechanisms
Although differentiating between innate and acquired resistance is vital from a scientific standpoint, the particular mechanisms of resistance are more relevant from a therapeutic perspective.
1.3.1 Increased Efflux of Drugs
It has been hypothesized that reduced intracellular drug accumulation as a result of increased anticancer agent efflux is the primary cause of chemotherapy resistance [7, 39, 40]. Excessive drug efflux rates may indicate innate or acquired resistance, depending on whether the problem appears before or after drug treatment.
The ABC transporter superfamily is the most common source of transmembrane transporters involved in drug efflux. There are 48 ABC genes in the human genome, and these genes have been divided into seven different subfamilies (ABCA-ABCG) [41, 42]. Among them, ABCB1, ABCC1, and ABCG2 play significant roles in the development of MDR to cancer chemotherapy.
Too far, ABCB1 (also known as MDR1 or P-gp) has been one of the best-studied ABC transporters. It consists of two nucleotide-binding domains that bind and hydrolyze ATP and two transmembrane domains that establish a passage for substrates. Transport substrates are pumped out as a result of conformational changes in the transporter that occur in conjunction with ATP binding and hydrolysis [43]. Etoposide, doxorubicin, paclitaxel, and vinblastine are only some of the many substrates that may be bound and pumped out of the cell by ABCB1 due to its many drug binding sites [44–48]. Numerous tumor forms, including kidney, lung, liver, colon, and rectum, have been shown to display high levels of ABCB1 prior to chemotherapy [49]. In contrast, numerous hematological malignancies, including AML and ALL, showed initially modest expression of ABCB1, followed by a substantial rise in expression of ABCB1 after chemotherapy [50–52].
ABCC1, also known as multi-drug resistance-associated protein 1 (MRP1), is responsible for the secretion of several different classes of anticancer drugs, including vinca alkaloids, anthracyclines, epipodophyllotoxins, camptothecins, and methotrexate [53]. Transported by ABCB1 include amphipathic and lipid-soluble molecules, whereas organic anionic substrates such as those conjugated to glutathione, glucuronide, or sulphate are pumped by ABCC1 [54–56]. ABCC1 overexpression has been linked to resistance in a variety of malignancies, including lung, breast, and prostate cancers [53, 57, 58].
In breast cancer, the protein ABCG2 (breast cancer resistance protein) is the primary drug efflux transporter responsible for the disease’s resistance to treatment. Some malignancies have been linked to ABCG2, a gene responsible for the so-called bystander population impact. A wide variety of medicines, including chemotherapeutics (mitoxantrone, bisantrene, epipodophyllotoxin, camptothecins, flavopiridol, and anthracyclines) and TKIs (imatinib and gefitinib), are transported by this transporter [48, 59, 60]. Overexpression of ABCG2 has been identified in a wide variety of cancers, including breast cancer, lung cancer, and leukemia [60, 61].
Additional insights into the mechanisms of drug resistance have been gleaned from studies of the substrates and activities of other ABC transporters involved in tumor resistance to anticancer drugs [62]. Overexpression of ABC transporter genes, such as ABCC2 and ABCC3, causes multi-drug resistance [62–65]. These genes are responsible for transporting a wide variety of chemotherapeutic medicines, including cisplatin, doxorubicin, and etoposide. ABC transporter mutations and overexpression have a direct impact on tumor sensitivity and the therapeutic value of anticancer medicines. Better medication selection and treatment results need an accurate and comprehensive expression profile of ABC transporters in malignancies.
1.3.2 Impact on Medication Target
Targeted treatments may impede the growth of cancer cells by blocking the action of particular target proteins involved in tumor formation, making them more selective and effective to cancer cells and less destructive to normal developing cells than typical chemotherapies. However, resistance may also emerge as an issue with targeted treatment, as a consequence of changes to medication targets. Secondary mutations in the target protein or changes in expression levels as a result of epigenetic modifications are two possible causes of medication target changes.
The epidermal growth factor receptor (EGFR) TKIs erlotinib and gefitinib, which are used to treat NSCLC, have reportedly shown a high response rate at the start of treatment [66, 67]. However, within a year, over half of the responding patients would have a T790M mutation on EGFR, leading to resistance to the first and second generations of TKIs [68–70]. The alteration in EGFR conformation brought about by the threonine-to-methionine mutation increased ATP binding affinity and decreased gefitinib/erlotinib binding to the kinase [70, 71]. Third-generation TKIs, such as osimertinib and rociletinib, have been developed and shown to have therapeutic effectiveness with patients having the T790M mutation [72, 73], hence overcoming the resistance conferred by this mutation. Resistance to third-generation inhibitors develops quickly, however, therefore developing fourth-generation TKIs is essential. The C797S mutation in EGFR has been identified as a potential mechanism of the novel resistance [74]. The binding of third-generation TKIs to EGFR is hindered by the absence of the cysteine residue, which is critical for TKIs to target the ATP site. As a result, EAI045, a fourth-generation TKI that targets both T790M and C797S, was developed to bind an allosteric site on EGFR to avoid the mechanism patterns of resistance seen with the first three generations of TKIs, all of which bind to the ATP sites [75, 76]. In the never-ending fight against drug resistance, a new trend may emerge the competition between the creation of new genetic mutations and the creation of new TKIs that restore drug sensitivity.
Such a case in which resistance is produced by a change in the therapeutic target is the creation and usage of oestrogen receptor inhibitors in the treatment of breast cancer. Commonly prescribed to those with ER-positive breast cancer, tamoxifen (TAM) works by competing with oestrogen for the ligand-binding site of ER. However, medication resistance is often developed after prolonged exposure to TAM. Mutations in the ER gene and decreased ER expression levels are two examples of resistance mechanisms that may occur in individual cases [77, 78]. Aromatase inhibitors (AIs) were created as a solution to the issues with TAM and the need for new medications. These treatments act by blocking the last stage in the production of oestrogen. In postmenopausal women with hormone receptor-positive breast cancer, third-generation AIs are increasingly employed as first-line therapy [79].
1.3.3 Improved DNA-Damage Repair
Chemotherapy medications, such as cisplatin and 5-fluorouracil (5-FU), cause cancer cells to die through DNA damage. Due to DNA lesion repairs, afflicted cells’ DNA damage response (DDR) to anti-cancer treatments may impair the medications’ effectiveness, leading to resistance [80]. For instance, 5-FU–resistant human colon cancer cell lines were discovered to have an upregulation of DNA repair genes, such as FEN1, FANCG, and RAD23B [81, 82]. Treatment with 5-FU led to the overexpression of genes involved in DNA damage response and repair that are p53 target genes. Cell cycle arrest and apoptosis were at lower levels in resistant cell lines compared to parental cell lines due to the successful healing of the damage [82].
While DNA damage response (DDR) downregulation might alleviate resistance caused by DNA repair, it also raises the prospect of acquiring additional mutations owing to genomic instability, the accumulation of which can spark a new cycle of carcinogenesis. As a result, the DNA damage response is a mechanism involved in cancer therapy and recurrence that needs careful examination before being employed as a therapeutic target in the fight against cancer.
1.4 Senescence Escape
Cellular senescence is defined as the permanent halt in cell growth that often results in the activation of tumor suppressive mechanisms controlled by p53 and/or p16INK4a [83]. Excessive mitogenic signaling from activated oncogenes, telomere shortening [84], and non-telomeric DNA damage from chemotherapeutic medicines are all important triggers that may induce cellular senescence. Chemotherapy drugs like doxorubicin and cisplatin, for instance, cause cell death and may also induce senescence [85, 86].
As previously mentioned, drug resistance and tumor recurrence/progression might occur as a result of tumor cells evading senescence induced by treatment (TIS) [87]. By acquiring stem-cell characteristics, cancer cells with TIS can avoid senescence and recurrence [88, 89].
1.5 Epigenetic Alterations
Epigenetic changes are an emerging mechanism that contributes to medication resistance. There is growing evidence that epigenetic alterations have a role in the development of resistance mechanisms such as improved drug efflux, accelerated DNA repair, and defective apoptosis [90–93].
DNA methylation, histone modification, chromatin remodeling, and changes to non-coding RNAs are all examples of epigenetic modifications [94]. Increased expression of an oncogene, for instance, would arise from demethylation of DNA in the gene’s promoter region, which might lead to resistance to treatment. Recent research showed that in a resistant hepa-tocellular carcinoma (HCC) cell line, the G-actin monomer binding protein thymosin 4 (T4) was enriched by demethylation of DNA and active modification of histone H3 at the promoter region [95]. The HCC cell line acquired stem cell-like properties with T4 overexpression, and the cells were resistant to the VEGFR inhibitor sorafenib in vivo [95].
Non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have a significant role in drug resistance [96, 97], in addition to chromosomal alteration. LncRNAs may be anywhere from 200 to over 10,000 nt in length, whereas miRNAs only have approximately 21 to 25 nt. As a result of binding to their corresponding mRNAs, miRNAs mediate mRNA degradation and suppress protein synthesis, earning them a prominent role as regulators of post-transcriptional gene expression. By inhibiting the binding of transcription activators to critical DNA regions in genes and by attracting chromatin remodeling proteins, LncRNAs play a role in the control of gene expression. The expression of proteins involved in cancer medication resistance is controlled by both microRNAs and long noncoding RNAs. It has been demonstrated, for instance, that cisplatin-resistant bladder cancer cells express higher levels of the lncRNA urothelial cancer-associated 1 (UCA1) than susceptible cells [98]. Increasing mRNA and protein levels of wingless-type MMTV integration site family member 6 (Wnt6) was shown to promote Wnt signaling and cell viability when UCA1 expression was upregulated [98].
1.6 Tumor Heterogeneity
Tumors exhibit four types of heterogeneity: genetic, cellular (cancer cells, stromal cells, immune cells, etc.), metabolic (oxygen/nutrient distribution), and temporal (dynamic tumor progression) [99]. Because of tumor heterogeneity, it is almost hard to eradicate all cancer cells with a singular therapy. Combinational therapy, such as FEC (5-fluorouracil, epirubicin, cyclophosphamide) for breast cancer, was developed as a solution to this issue. Here, the authors will discuss about the phenomenon of genetic diversity.
Primary tumors of several cancer types, including ovarian cancer [100], renal cell carcinoma [101], breast cancer [102], and chronic lymphocytic leukemia [103], have been demonstrated to house distinct subpopulations of cancer cells with distinct genetic profiles. Variable clonal variations of a tumor have different sensitivities to chemotherapy and targeted medications, meaning that early treatment can only eradicate some of the tumor while leaving others to persevere. If the resistant clones continue to multiply and expand, the tumor will reappear but this time with a new cell composition that is resistant to the original treatment. Evidence that the subclonal compositions vary dramatically at various periods of therapy [23, 24, 101, 104] lends credence to the idea that genetic heterogeneity of the subpopulations develops during drug treatment in a Darwinian selection way. Exosome-mediated transfer of microRNAs from drug-resistant tumor cells to drug-sensitive tumor cells may cause resistance in both types of tumor cells in heterogeneous tumor cell populations [105].
Studies documenting the decline in responsiveness to targeted medications provide credence to the idea that tumor heterogeneity plays a role in the development of treatment resistance. Targeted medicines have the potential to increase effectiveness and decrease adverse effects, but their high specificity may become a drawback when confronting tumor heterogeneity. Therefore, multi-drug combination therapy is necessary to either prevent tumor recurrence entirely or significantly slow its progression.
And since different individuals may react differently to the same medication, research into customized medicines is critically needed.
1.7 Tumor Microenvironment
Different cell types and the extracellular matrix (ECM) all have a role in the development, progression, and metastasis of tumors [106, 107]. The microenvironment of solid tumors consists of an extracellular matrix (ECM), immunological and inflammatory cells, blood arteries, fibroblasts, and numerous nutrients and signaling chemicals. Together, they play crucial roles in tumor development and survival.
TME has been linked to cancer’s innate resistance to treatment. The TME variables include pH. The pH outside of healthy tissue or cell is somewhat higher than the pH inside of it (pHe7.3–7.5 vs. pHi6.8–7.2) [108]. However, cancer cells raise internal pH and decrease external pH by pumping protons through proton transporters and modulating pH sensors [109, 110], creating a so-called reversed pH gradient. According to some research [111], cancer cells’ extracellular environment, which is often acidic (pH 6.5–7.1), may contribute to their resistance to chemotherapeutics. Cancer cells are able to avoid apoptosis because the distribution of weak base anticancer medications is hampered by the inverted pH gradient, a phenomenon known as “ion trapping” [112, 113]. The low extracellular pH that is increasingly being seen in solid tumors is a novel signature of these diseases that might be targeted in cancer treatment. Proton pump inhibitors (PPIs) and other therapeutic strategies that aim to lower the acidity of the microenvironment have been developed and proved to be effective in reducing tumor size and making cancer cells more sensitive to chemotherapy. One proton pump inhibitor (PPI) that has been shown to work synergistically with paclitaxel in melanoma cells in vitro and in vivo is lansoprazole [114].
Adaptation of cancer cells to chemo or targeted treatments, which reduces drug effectiveness and induces resistance, is also facilitated by post-treatment changes in the composition of TME. For instance, in the case of glioblastoma multiforme (GBM), a particularly deadly kind of brain tumor, TAMs contribute to the development of resistance to anticancer therapies [115]. To aid cancer cell growth and survival, macrophages in GBM tumors release large amounts of colony-stimulating factor-1 (CSF-1) [115, 116]. Cancer therapy that employs small molecule inhibitors or antibodies against CSF-1 receptor (CSF-1R) has shown encouraging in vivo effects [117–119]. Increased insulin-like growth factor-1 (IGF-1) production from TAMs and IGF-1–induced increase of phosphatidylinositol 3-kinase (PI3K) pathway signaling in glioblastoma multiforme (GBM) tumor cells contribute to the recurrence of GBM in over 50% of patients [115]. It has been shown in animal models that blocking both the CSF-1R and the IGF-1 receptor or PI3K signaling together increases survival time. Therefore, combination treatments that concurrently target cancer cells and TME may result in significantly increased anticancer effectiveness by lowering drug resistance.
Furthermore, TME heterogeneity enriches genetic heterogeneity, which is itself a facet of tumor heterogeneity. Variable hypoxia is one feature of the TME [120], which occurs because tumor vasculature is variable and dynamic. Oxidative stress caused by repeated hypoxia and reoxygenation may cause DNA damage in tumor cells, leading to an increase in mutations and the emergence of genetically distinct clonal subpopulations [121]. Further, as was previously indicated, cells in the TME, such as TAMs, contribute to tumor heterogeneity by interfering with the expression patterns of cancer cells by the release of exosomes carrying miRNAs [38].
As a result, TME is very important in tumor development and resistance to treatment. A more complete understanding of the TME and its interaction with tumor cells might significantly improve therapeutic response and clinical outcomes.
1.8 Epithelial to Mesenchymal Transition
The epithelial-to-mesenchymal transition (EMT) is a process in which epithelial cells change into mesenchymal stem cells by detaching from one another. While it is well established that EMT is necessary for the development of metastasis in cancers of epithelial origin, its involvement in other malignancies, such as sarcomas, is less well understood. There is mounting evidence that EMT is a key player in the development of resistance to chemotherapy. According to research conducted on an EMT lineagetracing mice model by Fischer et al., EMT enhances resistance to apoptotic induction initiated by the medication cyclophosphamide [122]. Recent research has shown that EMT and CSC have certain commonalities, and their involvements in drug resistance reflect various expressions of the same phenotype; however, the mechanisms of EMT-induced drug resistance are still not well understood. The Wnt, Notch, and Hedgehog signaling pathways are all shared by EMT cells and cancer stem cells (CSCs), suggesting a common mechanism [123]. In this way, EMT provides tumor cells a means to develop resistance to anticancer treatments and avoid the cell death that is normally produced by these medications. Among the best-studied important cytokines in EMT is transforming growth factor beta, whose signaling pathways are linked to acquired drug resistance [124, 125]. Reversing EMT and dramatically increasing cancer cells’ susceptibility to chemotherapies have both been linked to TGF- inhibition [126, 127]. Drug resistance has also been linked to the Wnt and Hedgehog pathways, according to the literature [128, 129].
In addition, there is mounting evidence that the EMT program is a crucial regulator of CSCs in mediating drug resistance. Epigenetic alterations triggered by EMT are necessary for cancer cells to enter the CSC state. The field of anticancer therapies would benefit greatly from research into the molecular relationship between EMT, CSCs, and drug resistance [130].
Transcription factors that induce EMT (EMT-TFs) also contribute to the development of drug resistance. Drug resistance may be induced by the overexpression of EMT-TFs [131–135], which include Twist, Snail, Slug, ZEB, and FOXC2. Recent research has shown that mice with pancreatic ductal adenocarcinoma treated with gemcitabine are more sensitive to the treatment andhave a higher survival rate when EMT is suppressed by knocking down EMT transcription factors Twist1 or Snail1 [136]. By facilitating ABC transporter-mediated drug efflux, several of these EMT-TFs contribute to resistance. Binding sites for EMT-TF were identified in the promoters of genes encoding ABC transporters [137]. Through increasing ABCB1 expression and activity, overexpression of Twist, ZEB1/2, Slug, and Snail causes drug resistance [138–140]. It is known that Snail, MSX2, SOX2, and ZEB1 control ABCG2, another ABC transporter intimately associated with MDR [141–144]. EMT-TFs have also been demonstrated to regulate other MDR-related ABC transporters, including ABCC1, ABCC2, ABCC4, and ABCC5. When it comes to paclitaxel-resistant nasopharyngeal cancer cells, for instance, overexpression of ABCC5 is linked to FOXM1. Depletion of FOXM1 or ABCC5 promotes paclitaxel-induced cell death and lowers drug efflux [145–148
