Apoptotic Pathway as the Therapeutic Target for Anticancer Traditional Chinese Medicines

Abstract

Cancer is a leading cause of morbidity and mortality worldwide. Apoptosis is a process of programmed cell death and it plays a vital role in human development and tissue homeostasis. Mounting evidence indicates that apoptosis is closely related to the survival of cancer and it has emerged as a key target for the discovery and development of novel anticancer drugs. Various studies indicate that targeting the apoptotic signaling pathway by anticancer drugs is an important mechanism in cancer therapy. Therefore, numerous novel anticancer agents have been discovered and developed from traditional Chinese medicines (TCMs) by targeting the cellular apoptotic pathway of cancer cells and shown clinically beneficial effects in cancer therapy. This review aims to provide a comprehensive discussion for the role, pharmacology, related biology, and possible mechanism(s) of a number of important anticancer TCMs and their derivatives mainly targeting the cellular apoptotic pathway. It may have important clinical implications in cancer therapy.

Keywords: apoptosis; cancer; cancer therapy; cellular signaling pathway; traditional Chinese medicine.

Figure 1

Mechanistic actions of apoptosis induction by traditional Chinese medicines (TCMs). Akt, protein kinase B; APF-1, ATP-dependent proteolysis factor 1; Bax, BCL2-associated X; Bcl, B cell lymphoma; Cyt c, cytochrome c; ERK1/2, extracellular regulated protein kinases; FADD, Fas associated death domain; IAPs, inhibitor of apoptosis proteins; IκBα, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha. JAK, Janus kinase; MAPK, mitogen-activated protein kinase; Mcl, myeloid cell leukemia sequence 1; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa B; PI3K, phosphatidylinositol-3 kinase; PARP, poly ADP-ribose polymerase; PTEN, phosphate and tension homology deleted on chromosome ten; Raf, rapidly accelerated fibrosarcoma; ROS, reactive oxygen species; RTK, receptor tyrosine kinase; STAT3, signal transducer and activator of transcription 3; TRADD, tumor necrosis factor (TNF) receptor associated death domain; XIAP, X-linked inhibitor of apoptosis protein.

Figure 2

Chemical structures of active compounds derived from anticancer TCMs that primarily activate caspase proteases.

Figure 3

Chemical structures of active compounds from anticancer TCMs that primarily affect Bcl-2/Bax signaling pathway.

Figure 4

Chemical structures of active compounds derived from anticancer TCMs that primarily inhibit NF-κB signaling pathway.

Figure 5

Chemical structures of active compounds derived from anticancer TCMs that primarily activate reactive oxygen species (ROS).

Figure 6

Chemical structures of active compounds derived from anticancer TCMs that primarily target PI3K/AKT/mTOR pathway.

Figure 7

Chemical structures of active compounds derived from anticancer TCMs that primarily target the Janus kinase (Jak)-signal transducer and activator of transcription 3 (STAT3) signaling pathway.

Figure 8

Chemical structures of active compounds derived from anticancer TCMs that target multiple apoptotic signaling pathways.