**Abstract**

The pathogenesis of many diseases is most closely related to inappropriate apoptosis (either too little or too much) and cancer is one of the situations where too little apoptosis happens, leading to 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. Several major molecular mechanisms are involved in the evasion of apoptosis in cancer initiation and progression. Bcl-2 family of proteins and caspases are the central players in the apoptotic mechanism and regulate cell death. Their imperfections cause to the deficient apoptotic signaling and thereby the inadequate apoptosis in cancer cells and eventually carcinogenesis. Strategies targeting these master regulators in carcinoma cells has been a major focus of interest in cancer studies. Therefore, despite being the cause of problem, apoptosis can be targeted in cancer therapy. This chapter provides a comprehensive review of apoptotic cell death and how deficiencies in apoptotic master regulators, caspases and Bcl-2 family proteins, influence carcinogenesis and can be targeted in cancer treatment.

**Keywords:** apoptosis, cancer, Bcl-2, caspase, regulation, dysfunction, intrinsic pathway, extrinsic pathway, carcinogenesis

## **1. Introduction**

Cancer as a complicated and heterogeneous disorder is the major threat to human beings and is still the significant leading cause of mortality around the world. According to the world health organization report, cancer is the second leading cause of death around the world with 9.6 million deaths in 2018. That is nearly 1 in 6 of all global deaths [1, 2]. The incidence of cancer is expected to rise approximately 70% within the next two decades around the world, from 14 million new cases in 2012 to 25 million new cases a year [3–5]. Cancer development comprises of a multiple steps happening progressively and beginning with initial mutations that promote tumorigenesis and, eventually, metastasis. The genetic alterations ultimately cause to a disturbance in the balance between cell proliferation and programmed cell death or apoptosis [6].

Apoptosis is a process of the cell's natural mechanism for death which occurred in multicellular organisms to maintain tissue homeostasis and act as a defensive strategy to remove infected, damaged or mutated cells. Apoptosis can be triggered through two major pathways, either mitochondrial- or death receptor-mediated pathways resulting from the intracellular (e.g. stress, DNA damage) and extracellular signals (death-inducing signals by other cells), respectively. This machinery

mainly depends on caspases cascades for executing cell death that eventually cause proteolytic cleavage of thousands of target proteins within the cells that are essential for normal cellular function such as cytoskeletal and nuclear proteins. Consequently, the apoptotic cells undergo a series of morphological and biochemical alterations leading to recognition by macrophages and cell phagocytosis. Moreover, B-cell lymphoma-2 (Bcl-2) family of proteins has long been identified for their significant involvement in regulating the cellular program of apoptosis through mitochondrial outer membrane permeabilization, as the critical decisionpoint at which cells commit to death, representing their vital role in protecting against cancer [7–9].

Deficiencies at any point along apoptotic pathways and dysfunction of the controlling mechanisms may result in impaired apoptosis that cause to carcinogenesis, allowing cancer cells to survive over intended lifespans and eventually uncontrolled cell proliferation, tumor development and progression. Tumor cells evade apoptosis through a variety of mechanisms. Understanding these molecular mechanisms not only provide insight into the cancer pathogenesis, but also provide clues on cancer treatment [7, 10]. Besides, genomic instability, nutrient deficiency, cellular hypoxia and oncogenic stress may cause to continuous stress within cancer cells which make them more sensitive to apoptotic stimulation. Hence, the ability to target the molecular components of this machinery and restore an apoptotic pathway has long been considered as an intriguing approach in cancer drug discovery. Consequently, being as a double-edged sword, apoptosis plays a critical role in both tumorigenesis and cancer therapy [6, 11, 12]. Therefore, as evasion of apoptosis is well known as the hallmark of all types of cancers, this chapter will be mainly emphasizing the role of apoptosis in cancer, from pathogenesis and cancer development to cancer therapy and treatment with primarily focus on two key mediators of apoptosis, caspases and Bcl-2 family of proteins, which have been receiving great attention in targeted cancer therapies.
