Anti-apoptotic protein Mcl-1 plays an important role in protecting cell from death in acute myeloid leukemia (AML). The apoptosis blocking activity of Mcl-1 is inhibited by BH3-only protein Noxa. We found that dihydroartemisinin (DHA) and its derivative X-11 are potent apoptosis inducers in AML cells and act through a Noxa-mediate pathway; X-11 is four-fold more active than DHA. DHA and X-11-induced apoptosis is associated with induction of Noxa; apoptosis is blocked by silencing Noxa. DHA and X-11 induce Noxa expression by upregulating the transcription factor FOXO3a in a reactive oxygen species-mediated pathway. Interfering with the integrity of the endoperoxide moiety of DHA and X-11, as well as chelating intracellular iron with deferoxamine, diminish apoptosis and Noxa induction. AML cells expressing Bcl-xL, or with overexpression of Bcl-2, have decreased sensitivity to DHA and X-11-induced apoptosis which could be overcome by addition of Bcl-2/Bcl-xL inhibitor ABT-737. DHA and X-11 represent a new group of AML cells-apoptosis inducing compounds which work through Noxa up-regulation utilizing the specific endoperoxide moiety and intracellular iron.
Unfavorable bioavailability is an
important aspect underlying the
failure of drug candidates. Computational approaches for evaluating
drug-likeness can minimize these risks. Over the past decades, computational
approaches for evaluating drug-likeness have sped up the process of
drug development and were also quickly derived to pesticide-likeness.
As a result of many critical differences between drugs and pesticides,
many kinds of methods for drug-likeness cannot be used for pesticide-likeness.
Therefore, it is crucial to comprehensively compare and analyze the
differences between drug-likeness and pesticide-likeness, which may
provide a basis for solving the problems encountered during the evaluation
of pesticide-likeness. Here, we systematically collected the recent
advances of drug-likeness and pesticide-likeness and compared their
characteristics. We also evaluated the current lack of studies on
pesticide-likeness, the molecular descriptors and parameters adopted,
the pesticide-likeness model on pesticide target organisms, and comprehensive
analysis tools. This work may guide researchers to use appropriate
methods for developing pesticide-likeness models. It may also aid
non-specialists to understand some important concepts in drug-likeness
and pesticide-likeness.
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