Table 1.

Apoptosis mechanism in cancer disease.

Protein	Up/down	Description	Article related to apoptosis	References
(1) Extrinsic pathway
FADD	Up	The key adaptor that transmits death signals via death receptors	Induction of apoptosis in HL-60 cells by luteolin necessitates FADD-caspase-8-mediated apoptosis	[12, 13]
FasL and Fas	Up	A critical death ligand and its receptor	Treatment with SCU, on the other hand, increases expression levels of Fas and Fas ligand (FasL) known to activate cleaved caspase-3, caspase-8, and polymeric adenosine diphosphate ribose (PARP) while decreasing the expression of death receptor 4 (DR4)	[12, 14]
TRAIL	Up	TNF family death ligand	Cancer cells are destroyed whereas primary esophageal cells are protected when primary esophageal cells are cultured in a mixed population with type I cancer cells and treated with TRAIL in the presence of a caspase-9 inhibitor	[12, 15]
DR4 and DR5	Up	Death receptors for TRAIL	Casticin enhances TRAIL-induced apoptosis by downregulating cell survival proteins and inducing DR5 via ROS	[12, 16]
(2) Intrinsic pathway
Bcl-2	Down	Regulate cell behavior through programmed cell death	The estrogenic actions of certain flavonoids may be responsible for upregulation of the Bcl2 gene in apoptotic MCF7 cells after flavonoid therapy	[17, 18]
BH3-only proteins	Up	To exert their intrinsic proapoptotic activities, all BH3-only molecules require multidomain BH3 proteins (Bax and Bak)	Phenoxodiol induces melanoma cell apoptosis by inducing p53-dependent BH3 proteins (PUMA, Noxa, and Bad) and p53-independent Bim protein, resulting in Bax activation and downstream events	[19, 20]
Bcl-xL	Down	Functions as apoptosis inhibitors	Fisetin, an HSF1 inhibitor, acts as a triple inhibitor, lowering expression levels of Bcl-2, Mcl-1, and Bcl-x L via downregulation of their chaperones, BAG3 and HSP70. As a result, fisetin might be beneficial in combating single agent-induced resistance	[17, 21]
BAX and BAK	Up	Results in the release of cytochrome c and activates caspases derived from mitochondria	Calycopterin treatment increases the Bax/Bcl2 ratio in HepG2 cancer cells, causing mitochondrial damage and subsequent cytochrome C release	[18, 19]
p53	Up	An important proapoptotic factor and tumor inhibitor	N101-2 treatment decreases expression levels of cyclin A and p-pRb while increasing expression levels of p53, p21, and p27	[19, 22]
(3) Caspase and caspase inhibitors
Caspase-8	Up	Initiator caspase that promotes the activation of caspase-3	The ligand binding to the transmembrane death receptor initiates the extrinsic apoptotic pathway, which leads in caspase-8 activation	[18]
Caspase-10	Up	Activation of signal transduction cascade is initiated by a caspase initiator	Caspase-10 is cleaved in response to flavone treatment	[17, 23]
Caspase-3	Up	Caspase effector	Fisetin activates caspase-3 and caspase-7 in a dose-dependent way. Such caspase activation coincides with PARP cleavage	[21]
IAPs (XIAP, cIAP1/2)	Down	Inhibitors of apoptosis proteins	Survivin, an inhibitor of apoptosis (IAP) family member, showed a reduction in expression following DHM therapy, perhaps due to p53 activation	[24]