Role of Nutraceuticals in Cancer Chemosensitization

Benjamin Bonavida

• Publisher: Academic Press
• Year: 2017
• eBook ISBN: 9780128123744
• Topic: Medicine
• Subtopic: Biotechnology in Medicine

Role of Nutraceuticals in Chemoresistance to Cancer, Volume Two, focuses on nutraceuticals, the compounds derived from natural sources, which are usually multi-targeted as a means to overcome chemoresistance. This book discusses the role of several compounds related to nutraceuticals and chemoresistance, such as curcumin, resveratrol, indole 3-carbinol, tocotrienols, ursolic acid, fisetin, celastrol, gambogic, butein, catechins and silymarin. It is a valuable resource for cancer researchers, oncologists and members of several areas of the biomedical field who are interested in understanding how to use nutraceuticals as a sensitizing agent for chemotherapy.- Brings updated information on natural compounds used as specific inhibitors of cell signaling pathways as reviewed by experts in the field- Presents experts analysis and summary of reported and novel findings and potential translational application in cancer patients- Describes molecular mechanisms with new and helpful approaches for the readers to use in their own investigations

Chapter 1

Pathways Linked to Cancer Chemoresistance and Their Targeting by Nutraceuticals

Alok Chandra Bharti*^,†; Kanchan Vishnoi^‡; Sukh Mahendra Singh^§; Bharat Bhushan Aggarwal^{¶ *} University of Delhi (North Campus), Delhi, India
^† National Institute of Cancer Prevention and Research - Indian Council of Medical Research (NICPR - ICMR), Noida, UP, India
^‡ University of Illinois, Chicago, IL, United States
^§ Banaras Hindu University, Varanasi, UP, India
^¶ Inflammation Research Center, San Diego, CA, United States

Abstract

Current strategy for cancer treatment involves surgery, radiotherapy, and chemotherapy. Among them, either chemotherapy is the only option or it is administered in conjunction with other modalities for treatment for almost all cancers. Anticancer drugs used for the treatment belong to diverse groups such as cell-cycle inhibitors, alkylating agents, antimetabolites, specific monoclonal antibodies, and small molecule inhibitors that can selectively target either rapidly proliferating cells or specific signature molecules on these cells. Naive tumors respond to these chemotherapeutic agents initially, but later, they develop resistance to most of these agents. This phenomenon makes tumors refractory, and management of the disease becomes difficult irrespective of the tumor type. Resistance may be intrinsic to the tumor clones or acquired during the course of treatment. Principal mechanisms of chemoresistance may include increased activity of the drug efflux transporters, decreased drug activation, altered drug targets, increased drug degradation, enhanced DNA-damage repair, and failure of cells to undergo apoptosis as a result of alterations in p53. Several attempts have been made by researchers to develop strategies to target chemoresistance. Among these, the use of nutraceuticals being most notable as they are safe and economic and have the capability of targeting multiple pathways of chemoresistance, and many of them also show independent anticancer activities. Taking this into consideration, several natural products are in different phases of clinical evaluation and have shown positive results in both preclinical and clinical studies. The results demonstrate that nutraceuticals may be developed as clinically useful anticancer chemosensitizers for adjuvant therapy in combination with existing chemotherapy to increase the treatment efficacy.

Keywords

Cancer; Chemoresistance; Chemotherapeutics; Apoptosis; DNA damage; Autophagy; Nutraceuticals; Phytochemicals; Drug efflux; Drug inactivation; Alkylating agents; Topoisomerase inhibitors; Cell-cycle inhibitors; Antimetabolites; Targeted therapy

Abbreviations

5-FU 5-fluorouracil

ABC ATP-binding cassette

AP-1 activator protein-1

BCRP breast cancer resistance protein

Caspases cysteine-aspartyl-proteases

CSC cancer stem cells,

CYP cytochrome P450

EGFR epidermal growth factor receptor

EMT epithelial mesenchymal transition

GST glutathione-S-transferase

MDR multidrug resistance

MDRPs multidrug resistance protein

NF-κB nuclear factor-kappa B

PDGFR platelet-derived growth factor receptor

STAT-3 signal transducers and activator of transcription 3

TS thymidylate synthase

UGT uridine diphospho-glucuronosyl transferase

VEGF vascular endothelial growth factor

Acknowledgments

The study was supported by extramural research grants from Department of Science and Technology (DST-PURSE Phase II/RC/2016/944); Department of Biotechnology, Government of India (Grant Support 6242-P34/RGCB/PMD/DBT/ALCB/2015); Indian Council of Medical Research (5/13/38/2014/NCD3); Department of Health Research, Ministry of Health and Family Welfare, Government of India; and intramural funding to ACB from University of Delhi.

Introduction

Cancer is a disease that develops overtime through accumulation of mutations and genetic changes in a cell. The characteristics distinguishing cancerous cells from the normal involve sustained proliferative ability, resistance to cell death, induction of angiogenesis, evasion of growth suppressors, limitless reproductive potential, ability to invade and metastasize, evade immune attack, genomic instability, inflammation, and continuous production of energy that are collectively designated as the “hallmarks of cancer” [1]. With improvements in longevity and decline of communicable diseases globally, an increase in the number of cancer cases has been observed, and a further increase is estimated in coming years [2]. Conventional approaches for the treatment of cancer include surgery, chemotherapy, and radiotherapy depending upon the cancer type and its clinical stage. Though the combinations and treatment regimens vary, in clinically advanced solid malignancies and hematopoietic cancers, chemotherapy is the upfront method of disease management.

Chemotherapy often employs a limited set of antineoplastic drugs of different categories for the treatment of most of the cancer types. These therapeutic agents principally target bulk of the tumor by killing cells with higher proliferation capacity and may leave behind slow proliferating or quiescent clone of cells that gradually get selected out and are responsible for relapse of drug-refractory tumors over a period of time. These secondary tumors are refractory to drugs initially used to treat cancer and may show a broad-spectrum drug resistance [3–9]. In recent times, several rationally designed anticancer drugs have been introduced that are derived against cancer-specific cellular/molecular targets. However, the use of these selective drugs to treat cancer also results in the development of chemoresistance though the mechanisms may be slightly different. Apart from the onset of chemoresistance, the standard chemotherapeutic drugs are highly toxic and with severe side effects and resulting in poor quality of life to the patient. The ability of cancer cells to develop drug resistance-associated toxicities and high cost of treatment demands an urgent need to develop new treatment strategies that could overcome chemoresistance and sensitize cancer cells to chemotherapy. At the same time, these new therapies should have less drug-associated toxicities and must be economic to cater patients with low resources.

One of the strategies to overcome chemoresistance could be to target specific molecular mediators using chemosensitizers that can be used in combination with existing chemotherapeutics for the better treatment outcome. Incidentally, the cancer cells can simultaneously employ multiple pathways and molecular mediators for manifestation of resistance. So, single target approach for chem...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• About the Editors
• About the Series Editor
• Aims and Scope for Series “Cancer Sensitizing Agents for Chemotherapy”
• Preface
• Chapter 1: Pathways Linked to Cancer Chemoresistance and Their Targeting by Nutraceuticals
• Chapter 2: The Potential of Curcumin: A Multitargeting Agent in Cancer Cell Chemosensitization
• Chapter 3: Role of Resveratrol in Chemosensitization of Cancer
• Chapter 4: Role of Tocotrienols in Chemosensitization of Cancer
• Chapter 5: Chemosensitization by Ursolic Acid: A New Avenue for Cancer Therapy
• Chapter 6: Role of Fisetin in Chemosensitization
• Chapter 7: Role of Celastrol in Chemosensitization of Cancer
• Chapter 8: Role of Gambogic Acid in Chemosensitization of Cancer
• Chapter 9: Role of Catechins in Chemosensitization
• Chapter 10: Anticancer Attributes of Silibinin: Chemo- and Radiosensitization of Cancer
• Chapter 11: Berberine as an Adjuvant and Sensitizer to Current Chemotherapy
• Chapter 12: Role of Emodin in Chemosensitization of Cancer
• Chapter 13: Role of Piperine in Chemoresistance
• Chapter 14: Role of Deguelin in Chemoresistance
• Chapter 15: Garcinol: Preclinical Perspective Underpinning Chemo- and Radiosensitization of Cancer
• Chapter 16: Chemopreventive and Anticancer Effects of Plumbagin: Novel Mechanism(s) via Modulation of Cellular Redox
• Chapter 17: Role of Zerumbone in the Chemosensitization of Cancer Cells
• Chapter 18: Multitalented Ginger and Its Clinical Development for Cancer Treatment
• Index