Lupane Triterpene Derivatives Improve Antiproliferative Effect on Leukemia Cells through Apoptosis Induction

Abstract

Leukemia is one of the most frequent types of cancer. No effective treatment currently exists, driving a search for new compounds. Simple structural modifications were made to novel triterpenes isolated from Phoradendron wattii. Of the three resulting derivatives, 3α-methoxy-24-hydroxylup-20(29)-en-28-oic acid (T1m) caused a decrease in the median inhibitory concentration (IC50) on the K562 cell line. Its mode of action was apparently apoptosis, ROS generation, and loss of mitochondrial membrane potential (MMP). Molecular docking analysis showed T1m to produce lower binding energies than its precursor for the Bcl-2 and EGFR proteins. Small, simple, and viable modifications to triterpenes can improve their activity against leukemia cell lines. T1m is a potentially promising element for future research. Clarifying the targets in its mode of action will improve its applicability.

Synthesis and Anticancer Activity of A-Ring-Modified Derivatives of Dihydrobetulin

“…At the same time, hydrophobic betulin and betulinic acid, the parent compounds of MK , directly affect the bioenergetics and membrane behavior of mitochondria isolated from the liver of Wistar rats [ 42 ]. MK may act in a similar way, but we could not exclude the modulation of apoptotic cascade due to oxidative stress by production of an abnormally high level of intracellular reactive oxygen species (ROS), which is also characteristic of triterpenoids [ 43 , 44 ]. Therefore, the ROS status was evaluated in the HBL-100/Dox cells after 4 h of exposure to MK , when a decrease in cell viability was not yet observed ( Figure 3 b), because apoptotic signs were only registered starting at 12 h ( Figure 4 b).…”

“…The results obtained are in good agreement with the supposition that ROS generation by triterpenoids leads to changes in the inner mitochondrial membrane, causing mitochondrial permeability and damaging its integrity. Consequently, the loss of MMP and the release of proapoptotic proteins into the cytosol, followed by the activation of the caspase cascade [ 43 , 44 ], is present.…”