Figure 13.

Schematic picture depicting cell death mechanisms of Piper genus-derived compounds. Escape of both intrinsic and extrinsic apoptosis is a common feature of cancer cells. (A) This hallmark is often carried out by overexpressing anti-apoptotic proteins, such as X-linked inhibitor of apoptosis protein (XIAP), which prevents the execution of apoptosis by binding of its baculovirus IAP repeat (BIR) 3 domain to already active initiator caspase 9. In order to counteract this resistance to cell death, several cancer pharmacological therapies have the aim of removing the ‘molecular brakes’ to apoptosis sensitising cancer cell to undergo loss of viability. The approach we described includes the use of three compounds from Piper genus plants which were predicted to bind XIAP-BIR3 domain. (B) Two of the compounds (gibbilimbol B and eriopodol A) were shown to induce a classical pro-apoptotic response, including mitochondrial outer membrane polarisation, release of cytochrome c, and subsequent activation of both initiator and effector caspases. (C) Despites triggering a similar response at the mitochondria level, erioquinol does not act through the apoptotic machinery, and results in a caspase-independent cell death characterised by cytoplasmic reactive oxygen species (ROS) accumulation.