Plant-derived Anticancer Drugs

Enhanced approaches for using plant-derived molecules as a more promising cancer treatment alternative, with lower costs and fewer side effects Plant-derived Anticancer Drugs discusses the current scenario of cancer, the limitations of synthetic drugs, and the potential of plant-derived molecules in cancer treatment, highlighting a variety of approaches, such as biodegradable nano and quantum dot-based materials, that enhance the therapeutic efficacy of plant-derived molecules to improve solubility, applicability, target-specific delivery, and overall efficacy. The book begins by discussing the preclinical and clinical utilization of synthetic drugs in cancer therapy, highlighting their mechanisms of action, therapeutic outcomes, limitations, and future perspectives. The book then provides a snapshot of the major drugs approved by the FDA which have historically served as the cornerstone of center treatment, and provides a clinical evidence-based analysis of their survival outcomes. Next, the current role, acceptance, advancements, and challenges of using plant-derived molecules in cancer therapy are reviewed. Contributed to by international experts in the field, Plant-derived Anticancer Drugs continues to cover sample topics including: Advancements in anti-cancer drug development due to genomics, biotechnology, and systems biology Integrative approaches which leverage the cytotoxic precision of synthetic drugs alongside the multitargeted and often less toxic nature of phytochemicals Optimization of phytochemicals with high anticancer potential to reduce drug discovery timelines and associated costs Integration of Artificial Intelligence (AI) and plant-derived bioactive compounds Ability of plant-derived molecules and herbal formulations to target multiple pathways involved in cancer progression, such as cell proliferation, apoptosis, angiogenesis, and metastasis Plant-derived Anticancer Drugs is a completely comprehensive and up-to-date reference on the subject, ideal for natural products chemists, medicinal chemists, biochemists, and cancer researchers in academia and industry. The book is also valuable reading for graduates and undergraduates studying nanotechnology, phytochemistry, pharmacology, oncology, and toxicology.

List of Contributors xvii Preface xxi 1 Utilization of Synthetic Drugs in Cancer: Preclinical and Clinical-based Evidence 1 Sandeep Vaidya, Avadh Biharee, Arpita Yadav, Arun Kumar Sharma, Akhlesh Kumar Jain, Suresh Thareja, and Mayank Kumar Singh 1.1 Introduction 1 1.1.1 Cancer Biology and Pathophysiology 2 1.1.2 Nanomedicine in Cancer Treatments 3 1.1.2.1 Applications of Nanomedicine in Cancer Treatment 5 1.1.3 Evolution of Synthetic Anticancer Drugs from Ancient Beliefs to Modern Medicine 6 1.2 Synthetic Pharmaceutical Anticancer Drugs 8 1.3 Challenges Faced in Early Drug Development 17 1.4 Conclusion 20 Acknowledgments 21 References 21 2 United States and European Union Regulations: Approved Treatment Modalities for Managing Cancer 29 Avadh Biharee, Khushi Gupta, Arpita Yadav, Shivam Kumar kori, Sudha Bhartiya, Kashif sheikh, Sandeep Vaidya, Sushil K. Kashaw, Suresh Thareja, and Mayank Kumar Singh 2.1 Introduction 29 2.2 FDA Strategies for Drug Approval in the United States 31 2.2.1 Expedited Approval of Anticancer Drugs in the United States 32 2.3 EMA Approach for Drug Approval in the EU 35 2.3.1 Expedited Anticancer Drug Approval in EU 36 2.4 Approved Treatment Modalities for Cancer Care 38 2.4.1 Conventional Cancer Therapy 39 2.4.2 Innovative Cancer Treatments 40 2.4.3 Physical Therapy for Cancer Treatment 41 2.4.4 Personalized and Precision Medicine 42 2.5 Quality Control in Cancer Treatment 43 2.6 Regulatory Frameworks Involved in Drug Approval Process 44 2.6.1 FDA and EMA Approach to Drug Approval for Cancer Treatment 45 2.6.1.1 Drug Approval in the United States 46 2.6.1.2 Drug Approval in the EU 46 2.6.2 Key Differences in the FDA and the EU Drug Approval Processes 48 2.6.3 Comparison of the United States and the EU Device Approval 50 2.7 Challenges Associated in Drug and Devices Regulation and Approval 52 2.8 Conclusion 53 Acknowledgments 54 References 54 3 Survival Rate and Associated Side Effects of Synthetic Drugs in Cancer Patients: A Shred of Clinical Evidence 63 Arpita Yadav, Arun Kumar Sharma, Kishan Kumar Pandey, Anu Chaudhary, Avadh Biharee, Sandeep Vaidya, Suresh Thareja, and Mayank Kumar Singh 3.1 Introduction 63 3.2 Synthetic Drugs in Cancer Treatment 65 3.3 The Evolution of Chemotherapeutic Agents from Alkylators to Modern Drugs 66 3.4 Cancer Survival Rates: Challenges and Emerging Trends in Treatment and Diagnosis 68 3.4.1 Targeted Therapies and Immunotherapies: The New Cancer Treatments 69 3.4.2 Factors Affecting Survival Rates 70 3.5 Deleterious Effects of Chemotherapeutic Agents and Their Management Strategies 72 3.6 Side Effects of Synthetic Drugs 74 3.6.1 Short-term Side Effects 74 3.6.2 Long-term Side Effects 75 3.7 Clinical Evidence of Side Effects 76 3.8 Resistance and Recurrence 76 3.9 Future Directions of Synthetic Drugs Against Various Types of Cancer 77 3.10 Conclusion 78 Acknowledgments 79 References 79 4 Global Perspectives on Plant-derived Cancer Therapies 91 Sayanta Sarkar and Poorwa Awasthi 4.1 Introduction 91 4.2 Phytochemicals in Cancer Therapies 92 4.2.1 Rosmarinus officinalis L. 93 4.2.2 Withania somnifera 95 4.2.3 Hedychium coronarium 97 4.2.4 Catharanthus roseus 99 4.2.5 Ocimum sanctum 100 4.2.6 Piper betle 102 4.3 Phytochemicals in Drug-resistant Cancers 103 4.4 Plant-based Nanomedicines in Cancer Therapies 103 4.5 Conclusion and Future Perspectives 104 References 106 5 Integrative Approaches: Combining Conventional and Plant-derived Cancer Therapies 119 Poorwa Awasthi, Shweta Goyal, and Sayanta Sarkar 5.1 Introduction 119 5.2 Conventional Cancer Therapies: Achievements and Limitations 120 5.3 Plant-derived Compounds in Cancer Therapy 124 5.3.1 Bioactive Molecules and Their Mechanisms 124 5.3.1.1 Polyphenols 124 5.3.1.2 Alkaloids 124 5.3.1.3 Terpenoids 125 5.4 Advantages of Natural Products 125 5.5 Synergistic Potential of Combination Therapies 128 5.5.1 Mechanisms of Synergy 128 5.5.2 Common Examples of Cancer with Combination Therapies 128 5.5.2.1 Breast Cancer 129 5.5.2.2 Lung Cancer 130 5.5.2.3 Colorectal Cancer 131 5.5.2.4 Prostate Cancer 132 5.5.2.5 Ovarian Cancer 133 5.5.2.6 Leukemia 135 5.5.2.7 Liver Cancer 136 5.5.2.8 Brain Cancer 138 5.6 Challenges and Future Perspectives 140 5.7 Conclusion 142 References 143 6 Phytochemical Drugs in Cancer: Therapeutic Interventions and Opportunities 159 Archana Kumari, Shankar Suman, and Shivam Priya 6.1 Introduction 159 6.2 Plant-derived Compounds in Cancer Therapy 160 6.2.1 Alkaloids and Their Anticancer Effects 161 6.2.2 Terpenoids as Potent Anticancer Agents 161 6.2.3 Flavonoids: Multifunctional Cancer Fighters 161 6.3 Mechanisms of Action of Plant-derived Compounds 162 6.3.1 Induction of Apoptosis 162 6.3.2 Targeting CSCs 162 6.3.3 Antiangiogenic Properties 163 6.3.4 Inhibition of Metastasis and Tumor Progression 163 6.4 Nanotechnology in Enhancing Plant-derived Compounds 164 6.4.1 Improving Bioavailability and Stability Through Nanoparticle Encapsulation 164 6.4.2 Targeted Delivery and Reduced Side Effects of Plant-derived Compounds 164 6.4.3 Overcoming Multidrug Resistance with Nanotechnology 164 6.5 Clinical Trials and Research on Plant-derived Anticancer Compounds 165 6.5.1 Clinical Trials of Curcumin in Cancer Therapy 165 6.5.2 Paclitaxel and Semisynthetic Taxanes 165 6.5.3 Flavonoids in Clinical Studies 166 6.6 Challenges and Future Directions in Plant-derived Cancer Therapies 166 6.6.1 Issues with Bioavailability and Solubility 166 6.6.2 Standardization and Quality Control 166 6.6.3 Clinical Validation and Regulatory Challenges 166 6.6.4 Potential of Bioinformatics in Drug Discovery 167 6.7 Advanced Applications of Bioinformatics in Plant-based Drug Discovery 168 6.7.1 Molecular Docking Studies and Predictive Modeling 168 6.7.2 Network Pharmacology Approaches 168 6.7.3 Genomics and Metabolomics in Identifying Novel Compounds 169 6.8 Case Studies of Successful Plant-derived Cancer Therapies 169 6.8.1 Green Tea Extracts in Clinical Applications 169 6.8.2 Vinca Alkaloids in Clinical Applications 169 6.8.3 Resveratrol’s Potential in Cancer Therapy 170 6.9 Future Perspectives and Integration into Clinical Oncology 171 6.9.1 Development of Combination Therapies 171 6.9.2 Role of Personalized Medicine 171 6.9.3 Advanced Drug Delivery Systems 171 6.10 Conclusion and Future Directions 172 References 174 7 Plant-derived Anticancer Molecules as Novel Outlook in the Management of Cancers: An In silico and Pharmacophore-based Approaches 183 Surya Venkateswara Prabhu Ratnam Kesanapalli, Babli K. Jha, and Laxmi Devi 7.1 Introduction 183 7.2 Historical Perspective 184 7.3 Key Discoveries of Plant-derived Anticancer Compounds 184 7.4 Phytochemicals with Anticancer Properties 185 7.4.1 Alkaloids 185 7.4.2 Flavonoids 186 7.4.3 Terpenes 187 7.4.3.1 Paclitaxel (Taxol) 187 7.4.3.2 Limonene 187 7.4.3.3 Phenolics 187 7.4.3.4 Polyphenols 187 7.4.3.5 Saponins 188 7.4.3.6 Lignans 188 7.5 Computational Approaches in Phytochemical Research 188 7.5.1 In silico Docking Analysis 189 7.5.2 Virtual Screening 190 7.5.3 Quantitative Structure-Activity Relationship 190 7.5.4 Structure-based Screening Method 191 7.5.5 Molecular Dynamics Simulations 192 7.5.6 Cheminformatics 192 7.5.7 Pharmacophore Modeling 192 7.5.8 ml and AI in Drug Discovery 193 7.6 Novel Therapeutic Approaches 193 7.6.1 Phytochemical-based Drug Formulations 193 7.6.2 Immunotherapy 194 7.6.3 Targeted Therapy 194 7.6.4 Nano Catalysts 194 7.6.5 Combination Therapies 194 7.6.6 Personalized Medicine 195 7.6.7 Advanced Drug Delivery Systems 195 7.7 Challenges and Future Directions 196 7.8 Bioavailability Issues 196 7.9 Regulatory Hurdles 196 7.9.1 Ethical Considerations and Sustainable Sourcing 197 7.10 Advancements in Computational Power and Algorithms 197 7.10.1 Quantum Computing 197 7.10.2 Explainable AI 198 7.10.3 Precision Oncology 199 7.10.4 Biomarker Discovery 199 7.11 Conclusion 200 Acknowledgment 201 References 202 8 Plant-derived Molecules and Herbal Formulation for Cancer Treatment: in vitro and in vivo Evidence 209 Surya Venkateswara Prabhu Ratnam Kesanapalli, Babli K. Jha, and Laxmi Devi 8.1 Introduction 209 8.2 Historical Use of Herbal Remedies in Cancer 210 8.3 Natural Compounds with Anticancer Properties 211 8.3.1 Alkaloids 212 8.3.2 Flavonoids 214 8.3.3 Terpenoids 214 8.3.4 Polyphenols 215 8.3.5 Saponins 215 8.3.6 Lignans 215 8.4 Mechanism of Action 215 8.5 Natural Remedies in Cancer Treatment 216 8.6 Phototherapeutic Approaches in Oncology Care 218 8.7 Methodological Approaches 220 8.7.1 In silico Studies (Computational Approaches) 220 8.7.2 Network Pharmacology 221 8.7.3 In vitro Studies (Cell-based Assays) 221 8.7.3.1 Cytotoxicity Assays (MTT, Trypan Blue, LDH Assay) 221 8.7.3.2 Lactate Dehydrogenase Release Assay 221 8.7.4 Apoptosis and Cell Cycle Analysis 221 8.7.5 Caspase Activation Assays 221 8.7.6 Proliferation and Migration Assays 221 8.7.6.1 Bromodeoxyuridine or 5-Ethynyl-2’-deoxyuridine Incorporation Assays 221 8.7.6.2 Scratch Wound Healing Assay 222 8.7.7 Caco-2 Permeability Assay 222 8.7.8 Western Blot and Reverse Transcription-Polymerase Chain Reaction 222 8.7.9 Wound Healing and Transwell Migration Assays 222 8.8 In vivo Studies (Animal Models) 222 8.8.1 Xenograft Models 222 8.8.2 Genetically Engineered Mouse Models 222 8.8.3 Toxicity and Pharmacokinetics Studies 222 8.8.4 Xenograft Tumor Models 222 8.8.5 GEMMs in Drug Resistance Studies 223 8.8.6 Patient-derived Xenograft Models 223 8.9 Ex Vivo and 3D Models 224 8.9.1 Patient-derived Organoids 224 8.9.2 3D Spheroid Cultures 224 8.10 Clinical Trials and Translational Research 224 8.10.1 Phases I–III Clinical Trials 224 8.10.2 Combination Therapy Studies 224 8.11 Nanotechnology-based Delivery Systems 224 8.12 Experimental Validation of Computational Predictions 224 8.12.1 Machine Learning and Artificial Intelligence in Drug Discovery 225 8.12.2 Biophysical and Biochemical Binding Assays 225 8.12.3 Advanced Experimental Approaches 226 8.12.4 Immunomodulatory Approaches 226 8.12.5 Pharmacophore-based Approaches 226 8.12.5.1 Targeting Specific Interactions 226 8.12.5.2 Guiding Virtual Screening 227 8.12.5.3 Enhancing Lead Optimization 227 8.12.5.4 Reducing False Positives/Negatives 227 8.13 Key Findings 228 8.14 Challenges and Future Directions 228 8.14.1 Challenges in Standardization and Bioavailability 228 8.14.2 Natural Compounds for Supportive Cancer Care 228 8.15 Future Studies and Clinical Trials 229 8.16 Conclusion 229 Acknowledgment 229 References 230 9 Globalization of Plant-derived Molecules Against Progression and Metastasis of Cancer in the Last Few Decades 239 Kavita, Praveen Kumar, Shikha Singh, and Neha Garg 9.1 Introduction 239 9.2 Plant-derived Molecules in Cancer 240 9.2.1 Alkaloids 240 9.2.1.1 Camptothecin 240 9.2.1.2 Berberine 251 9.2.1.3 Evodiamine 251 9.2.1.4 Sanguinarine 252 9.2.1.5 Matrine 252 9.2.1.6 Piperine 253 9.2.1.7 Vinblastine and Vincristine 253 9.2.1.8 Tetrandrine 253 9.2.2 Polyphenols 254 9.2.2.1 Flavonoids 254 9.2.2.2 Phenolic Acids 259 9.2.2.3 Stilbenes 259 9.2.2.4 Lignans 260 9.2.3 Taxanes and Epipodophyllotoxins 261 9.2.3.1 Paclitaxel 261 9.2.3.2 Docetaxel 261 9.2.4 Glycosides 262 9.2.4.1 Rutin 262 9.2.4.2 Verbascoside 262 9.2.4.3 Russelioside 262 9.3 Conclusion and Future Perspectives 263 List of Abbreviations 263 Conflict of Interest 263 Acknowledgment 264 References 264 10 Quantum Dots for Targeted Delivery of Plant-derived Anticancer Biomolecules 279 Rashmi P. Sharma 10.1 Introduction 279 10.2 Quantum Dots: A Promising Nanomaterial 283 10.2.1 Types of QDs 283 10.2.1.1 Core-type QDs 284 10.2.1.2 Core-shell QDs 284 10.2.1.3 Alloyed QDs 284 10.2.2 Advantageous Properties of QDs for Targeted Drug Delivery 285 10.3 Cellular Delivery of Cancer-targeting QDs 286 10.4 Recent Developments in Using QD-based Targeted Drug Delivery 288 10.4.1 Taxanes 290 10.4.2 Alkaloids 291 10.4.3 Polyphenols 293 10.4.4 Flavonoids 295 10.4.5 Other Plant-derived Anticancerous Compounds 296 10.5 Challenges and Future Perspectives 297 10.6 Conclusions 299 References 299 11 Future of Artificial Intelligence and Plant-derived Molecules in Cancer Therapy 313 Jyotika Rajawat, Shreya Prakash, and Poorwa Awasthi 11.1 Introduction 313 11.2 Plant-derived Molecules in Cancer Therapy 315 11.2.1 Camptothecin 315 11.2.2 Taxol 316 11.2.3 Anthocyanins 316 11.2.4 Phytosphingosine 317 11.2.5 Genistein 317 11.3 Natural Plant Extracts with Potential as Anticancer Agents 319 11.3.1 Fagonia indica 320 11.3.2 Aristolochia baetica 320 11.3.3 Catharanthus roseus 321 11.3.4 Curcuma longa 322 11.3.5 Artemisia annua 322 11.4 AI in Cancer Diagnosis and Treatment 323 11.5 Role of AI in Advancing Plant-derived Molecules for Cancer Therapy 327 11.5.1 High-throughput Screening of Phytochemicals 327 11.5.2 Toxicity Prediction and ADMET Profiling 328 11.5.3 Target Identification and Validation 330 11.5.4 Optimization of Drug Design 331 11.5.5 Drug Repurposing 332 11.6 Future Perspectives 332 References 333 12 Scientific Basis of Plant-derived Quantum Dots for Enhancing the Therapeutic Efficacy in Cancer 341 Lucky Kumari, Shashi Kumar, Chandramani Batsh, Shachi Mishra, and Akanksha Upadhyay 12.1 Introduction 341 12.2 Classification of QDs 344 12.3 Synthesis of Plant-derived QDs 346 12.3.1 Hydrothermal Method 347 12.3.2 Microwave Method 348 12.3.3 Chemical Oxidation Method 348 12.3.4 Pyrolysis Method 349 12.4 Plant-derived QDs in Cancer Diagnosis and Therapy 352 12.4.1 In vitro Cytotoxicity 352 12.4.2 In vivo Cytotoxicity 353 12.5 Therapeutic Efficacy 354 12.5.1 Photo-induced Cancer Treatment 355 12.5.2 Gene Therapy 356 12.5.3 Immunotherapy 357 12.6 Conclusion and Future Perspectives 359 References 360 13 Clinical Trials of Plant-derived Molecules and Herbal Formulations for the Treatment of Cancers 367 Ankur Kumar 13.1 Introduction 367 13.2 Clinical Trials of Curcumin 368 13.3 Clinical Trials of Catechin and Tea 373 13.4 Clinical Trials of Quercetin 379 13.5 Clinical Trials of Ginseng Extract 380 13.6 Clinical Trials of Genistein 381 13.7 Clinical Trial of Resveratrol 382 13.8 Clinical Trials of Sulforaphane 383 13.9 Clinical Trials of Berberine 384 13.10 Clinical Trials of Lycopene 385 13.11 Clinical Trials of Chinese Herbal Formulation 386 13.12 Clinical Trials of Other Herbal Formulation 393 13.13 Clinical Trials of Rutin 395 13.14 Clinical Trials of Betulinic Acid 395 Competing Interest 396 References 396 14 Preclinical and Clinical Trials of Plant-derived Nanoparticles in Different Cancers 401 Vivek Kumar Pandey and Shailja Tripathi 14.1 Introduction 401 14.2 Synthesis of Plant-derived Nanoparticles 402 14.2.1 Advantages of Plant-derived Nanoparticles 404 14.3 PDNPs in Cancers 405 14.3.1 Plant-derived Nanoparticles in Cancer Treatment 406 14.3.2 Advantages of Plant-derived Nanoparticles in Cancer Treatment 409 14.3.3 PDNPs’ Mechanisms of Action in Cancer Therapy 409 14.3.4 Plant-derived Nanoparticles in Cancer Therapy 410 14.3.5 PDNPs in Clinical Trials for Cancer Treatment 411 14.4 PDNPs in Other Metabolic Diseases 411 14.5 Challenges and Future Directions 413 References 414 Index 427