Abstract
Ingenol mebutate possesses significant cytotoxicity and is clinically used to treat actinic keratosis. However, ingenol mebutate undergoes acyl migration which affects its bioactivity. Compound 3-O-angeloyl-20-O-acetyl ingenol (AAI, also known as 20-O-acetyl-ingenol-3-angelate or PEP008) is a synthetic derivative of ingenol mebutate. In this work, we report the AAI synthesis details and demonstrate AAI has higher cytotoxicity than ingenol mebutate in a chronic myeloid leukemia K562 cell line. Our data indicate that the increased activity of AAI originates from the improved intracellular stability of AAI rather than the increased binding affinity between AAI and the target protein protein kinase Cδ (PKCδ). AAI inhibits cell proliferation, induces G2/M phase arrest, disrupts the mitochondrial membrane potential, and stimulates apoptosis, as well as necrosis in K562 cells. Similar to ingenol mebutate, AAI activates PKCδ and extracellular signal regulated kinase (ERK), and inactivates protein kinase B (AKT). Furthermore, AAI also inhibits JAK/STAT3 pathway. Altogether, our studies show that ingenol derivative AAI is cytotoxic to K562 cells and modulates PKCδ/ERK, JAK/STAT3, and AKT signaling pathways. Our work suggests that AAI may be a new candidate of chemotherapeutic agent.
Highlights
Ingenol mebutate is a hydrophobic diterpene ester which is isolated from the sap of the plant Euphorbia peplus
AAI inhibited the cellular proliferation, unlike most of other chemical agents, the inhibition on the cell proliferation was not in a concentration-dependent manner. This concentration independence of AAI was similar to its parent compound ingenol mebutate [13,14], and the possible reason for this could be partly due to the toxic effect, as this kind of compounds could induce both necrosis and plasma membrane disruption, in addition to the apoptosis [13]
We found that AAI arrested K562 cells at G2/M phase and induced mitochondrial apoptosis in K562 cell line, which is Bcr-Abl promoted chronic myeloid leukemia
Summary
Ingenol mebutate ( called PEP005 or ingenol 3-anglate, Figure 1A) is a hydrophobic diterpene ester which is isolated from the sap of the plant Euphorbia peplus. SSiimmiillaarrllyy,, AAAAII ((225500 nnmm)) ttiimmee--ddeeppeennddeennttllyy iinnccrreeaasseedd tthhee ggrreeeenn flfluuoorreesscceennccee aanndd ddeeccrreeaasseedd tthhee rreedd flfluuoorreesscceennccee ((FFiigguurree 44BB)),, ffuurrtthheerr ccoonnfifirrmmiinngg tthhee ddiissrruuppttiioonn ooff MMMMPP iinn KK556622 cceelllsls. AAI inhibited the cellular proliferation, unlike most of other chemical agents, the inhibition on the cell proliferation was not in a concentration-dependent manner This concentration independence of AAI was similar to its parent compound ingenol mebutate [13,14], and the possible reason for this could be partly due to the toxic effect, as this kind of compounds could induce both necrosis and plasma membrane disruption, in addition to the apoptosis [13]. The parent compound ingenol mebutate has been shown to induce apoptosis in leukaemic cell lines, an effect that requires the expression of protein PKCδ. Since AAI could regulate multiple signaling molecules as presented in this work, it will be interesting to perform the global arrays to illustrate the changes in signaling pathways after AAI treatment in future studies
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