Regulation and interplay of apoptotic and non‐apoptotic cell death

Abstract

Various death triggers including DNA damage, oxidative stress, and growth factor deprivation promote the loss of mitochondrial membrane potential, leading to the production of reactive oxidative species (ROS) or enhanced permeability of the mitochondrial membrane, otherwise known as mitochondrial membrane permeabilization, by insertion of Bax/Bak into the outer membrane where it interacts with voltage-dependent anion channel (VDAC)/adenine nucleotide transporter (ANT). MMP leads to the release of small pro-apoptotic molecules, which induce caspase-dependent and -independent apoptotic cell death. The production of ROS due to the loss of mitochondrial membrane potential enhances the permeability of lysosomal membranes, resulting in the release of lysosomal proteases, which contribute to mitochondrial membrane permeabilization and the lysosomal degradation mechanism of autophagic cell death. Although defects in apoptotic and non-apoptotic cell death pathways can be carcinogenic, these pathways are more or less preserved within cancer cells and can therefore influence cell death and mediate resistance to cancer treatment. This paper discusses recent advances in determining the molecular mechanisms behind regulation of apoptotic and non-apoptotic cell death, as well as the interplay between these two processes, which may lead to the development of new strategies by which to enhance the therapeutic effects of chemotherapeutic agents.

A novel indole ethyl isothiocyanate (7Me-IEITC) with anti-proliferative and pro-apoptotic effects on platinum-resistant human ovarian cancer cells

“…Within 3hrs of 7-MeIEITC treatment we observed a loss of mitochondrial transmembrane depolarization potential (ΔΨm) in SKOV-3 cells as reported for other ITC derivatives [21]. The ADP:ATP ratio and ΔΨm can be used as an indicator of apoptosis [22,23]. Moreover, the loss of ΔΨm due to chemical agents for other drug-treated cell types has been reported to be indicator of early apoptosis and as the first irreversible step in the induction of apoptosis [24].…”

miR-145 induces caspase-dependent and -independent cell death in urothelial cancer cell lines with targeting of an expression signature present in Ta bladder tumors

“…Whether these pathways are activated in parallel or function in redundancy is unknown. The existence of an interplay between apoptotic and non-apoptotic cell death in cancer cells is well known (Kim et al, 2006). For example, TRAIL induces apoptosis in lung carcinoma A549 cells at normoxic levels and non-apoptotic death at hypoxia at which Bcl-2, Bcl-XL, and Inhibitor of apoptosis proteins are upregulated (Kim et al, 2004).…”

“…In addition, cells are sensitized to TNF-a-induced cell death in the presence of zVAD-fmk that arrest apoptosis and promote other forms of cell death, such as autophagic cell death (Yu et al, 2004). As genetic alterations in cell death pathways enable cancer cells to evade cell death eventually leading to tumor progression (Hanahan and Weinberg, 2000;Kim et al, 2006), effective induction of multiple types of cell death may increase the therapeutic efficacy of anticancer agents. Thus, from a clinical therapeutic perspective, it is interesting that miR-145 induces multiple death pathways.…”

Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo

“…Thus, it was shown that NOaspirin was capable to induce apoptosis in colon cancer cells, whereas the other drug, NO-sulindac, was responsible for apoptotic death of bladder and prostate carcinoma (9,10). Several evidences indicate that the capacity of the tumor cells to develop resistance to pharmacologically induced apoptosis plays a key role in determining their resistance to chemotherapy (32). This phenomenon could be explained by the overexpression of signaling molecules with antiapoptotic properties (33).…”