Didesmethylrocaglamide

Little research has been conducted specifically regarding didesmethylrocaglamide, but its mechanism of action is likely to be congruent with the rest of the rocaglamide class.

Didesmethylrocaglamide’s anti-tumor activity, similar to other rocaglamide derivatives, is driven primarily via inhibition of protein synthesis in tumor cells. Inhibition of protein synthesis is accomplished via inhibition of prohibitin 1 (PHB1) and prohibitin 2 (PHB2) - these proteins are necessary in the proliferation of cancer cells and are implicated in the Ras-mediated CRaf-MEK-ERK signaling pathway responsible for phosphorylating eIF4E, a key factor in the initiation of protein synthesis. There is also some evidence that rocaglamides can act directly on eIF4A, another translation initiation factor of the eIF4F complex ultimately responsible for initiation of protein synthesis.

Inhibition of protein synthesis has a number of downstream effects. Many of the proteins that are down-regulated in response to protein synthesis inhibition in tumor cells are short-lived proteins responsible for regulation of the cell cycle, such as Cdc25A. Cdc25A is an oncogene that can become overexpressed in certain cancers and lead to unchecked cell growth. In addition to inhibiting its synthesis via the mechanism described above, rocaglamides promote degradation of Cdc25A via activation of the ATM/ATR-Chk1/Chk2 checkpoint pathway. This pathway is normally activated in response to DNA damage and serves to reduce the expression of proteins responsible for cell cycle progression, thereby inhibiting proliferation of damaged (i.e. tumour) cells. Inhibition of protein synthesis also appears to prevent the actions of the transcription factor heat shock factor 1 (HSF1), leading to an increased expression of thioredoxin-interacting protein (TXNIP) which is negatively regulated by HSF1. TXNIP is a negative regulator of cell glucose uptake, and its increased expression blocks glucose uptake and consequently impairs the proliferation of malignant cells.

Rocaglamides also appear to induce apoptosis in tumor cells via activation of the pro-apoptotic proteins p38 and JNK and inhibition of the anti-apoptotic Mcl-1 protein. Similarly, they have been studied as an adjuvant in TRAIL-resistant cancers due to their ability to inhibit the synthesis of c-FLIP and IAP/XIAP - these anti-apoptotic proteins can become elevated in certain cancers, preventing the induction of apoptosis and resulting in resistance to TRAIL-based therapies.