Preface

The pathogenesis of many diseases is most closely related to inappropriate apoptosis. For example, cancer is one of the situations where too little apoptosis leads to the development of malignant cells that highly proliferate. Defects at any points along apoptotic pathways may lead to malignant transformation of the affected cells, tumor metastasis, and resistance to anti-cancer drugs. Strategies targeting the master regulators in carcinoma cells have been a major focus of interest in cancer studies. Therefore, despite being the cause of the problem, apoptosis can be targeted in cancer therapy.

 This book begins with Chapter 1, "The Role of Apoptosis as a Double-Edge Sword in Cancer," which provides a comprehensive review of apoptotic cell death and examines how deficiencies in apoptotic master regulators, caspases, and Bcl-2 family proteins influence carcinogenesis and can be targeted in cancer treatment. Chapter 2, "The Program Cell Death (Apoptosis) and The Therapy of Cancer," deals with apoptosis's vital roles in maintaining organ homeostasis. Programmed cell death occurs when the DNA damage is irremediable and has two important pathways: the intrinsic death pathway, also known as the mitochondrial pathway, and the extrinsic programmed cell death pathway. Any defects in the regulation of these crucial pathways have been associated with many disorders, most importantly cancer. Therefore, understanding the molecular basis of apoptosis is essential for the treatment of incurable cancer. Hence, it is important to understand the maintenance and counteraction of apoptosis and develop and improve successful new pharmacological applications of cell death mechanisms for future therapies. This chapter discusses the mechanism of apoptosis and emerging principles of drug resistance in cancer. Chapter 3, "Recent Advancements in Apoptosis-Based Therapeutic Approaches for Cancer Targeting," discusses the development of novel drug targets and drug delivery systems for inhibiting or inducing apoptosis. Apoptosis plays a major role in cellular homeostasis, normal development, and clearance of cells. Non-programmed cell death can take place by various external factors, such as infection, toxins, and physical injury. The chapter provides recent insights into therapeutic approaches to cancer. Chapter 4, "Insights into the Role of Defective Apoptosis in Cancer Pathogenesis and Therapy," discusses defective apoptosis as an indispensable causative factor in the development of cancer that allows cancer cells to survive longer and favors the accumulation of oncogenic mutations. Further, upregulation of anti-apoptotic proteins and loss of pro-apoptotic proteins strongly favors apoptosis evasion. The ability of cancer cells to evade apoptosis is critical for the progression and clonal expansion of malignantly transformed cells. Defective apoptosis imparts proliferative advantage to cancer cells or cells with the potential to become cancerous. The mechanisms employed by cancer cells to evade apoptosis can be used in the strategic design of therapeutic regimens aimed at exploiting apoptotic signaling networks to ensure tumor-specific cell death. This chapter presents knowledge about the molecular mechanisms of defective apoptosis that could be translated into the development of novel therapeutic agents and therapeutic modalities for cancer treatment. Chapter 5, "Efferocytosis: An Interface between Apoptosis and Pathophysiology," deepens our understanding of cellular death mechanism. Cell death occurring under physiological conditions is primarily

caused by apoptosis, which is a non-inflammatory or silent process, whereas necroptosis or pyroptosis is triggered by pathogen invasion, which stimulates the immune system and induces inflammation. In physiology, clearing dead cells and associated cellular debris is necessary since billions of cells die during mammalian embryogenesis and every day in adult organisms. For degradation, dead cells produced by apoptosis are quickly engulfed by macrophages. This chapter presents a description of the phagocytosis of dead and dying cells, as a process known as efferocytosis. Chapter 6, "Programmed Cell Death (PCD) in Plant: Molecular Mechanism, Regulation and Cellular Dysfunction in Response to Development and Stress," highlights the current understanding of plant programmed cell death in terms of different pathways, cellular responses, regulation, and signaling mechanisms. The study helps to understand the molecular and structural instincts of programmed cell death in different stages of plant growth and development, response to biotic/abiotic stimuli, and cellular dysfunction. Chapter 7, "Regulation of Apoptosis during Environmental Skin Tumor Initiation," discusses skin cancer. Skin cancer has three distinct stages: initiation, promotion, and progression. During the initiation, the fate of DNA-damaged skin cells is determined by the homeostatic regulation of pro-apoptotic and anti-apoptotic signaling pathways. The imbalance or disruption of either signaling will lead to the survival of initiated cells, resulting in the development of skin cancer. This chapter elaborates on the signaling pathways that regulate apoptosis and the impact of their dysfunction during skin tumor initiation. Finally, Chapter 8, "The Interplay of Key Phospholipid Biosynthetic Enzymes and the Yeast V-ATPase Pump and Their Role in Programmed Cell Death," covers a model organism apoptotic mechanism. Exposure of the yeast *Saccharomyces cerevisiae* to environmental stress can influence cell growth, physiology, and differentiation, and thus result in cells' adaptive response. During the course of adaptive response, the yeast vacuoles play an important role in protecting cells from stress. The vacuole is a dynamic organelle and is similar to lysosomes in mammalian cells. The defect of the lysosome's function may cause various genetic and neurodegenerative diseases. The multi-subunit V-ATPase is the main regulator for vacuolar function and its activity plays a significant role in maintaining pH homeostasis. V-ATPase is an ATP-driven proton pump required for vacuolar acidification. It has also been demonstrated that phospholipid biosynthetic genes might influence vacuolar morphology and function. However, the mechanistic link between phospholipid biosynthetic genes and vacuolar function has not been established. Recent studies have demonstrated the regulatory role of Pah1p, a phospholipid biosynthetic gene, in V-ATPase disassembly and activity. Therefore, this chapter employs *S. cerevisiae* as a model to show how Pah1p affects V-ATPase disassembly and activity and how Pah1p negatively affects vacuolar function.

> **Dr. Yusuf Tutar** Professor, Department of Basic Pharmaceutical Sciences, Division of Biochemistry, Hamidiye Faculty of Pharmacy, University of Health Sciences-Turkey, Istanbul, Turkey

Section 1
