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Honokiol-Chlorambucil Co-Prodrugs Selectively Enhance the Killing Effect through STAT3 Binding on Lymphocytic Leukemia Cells In Vitro and In Vivo
journal contribution
posted on 2020-07-29, 11:40 authored by Li Xia, Dali Kang, Dan Wan, Chu Chu, Meizi Chen, Shuihan Zhang, Xiong Li, Leye He, Jianye Yan, Teng Liu, Yongbo PengThe broad-spectrum DNA alkylating
therapeutic, chlorambucil (CBL),
has limited safety and shows lower therapy effect because of a short
half-life while used in the clinic. Therefore, it is very necessary
to develop a more efficient and safer type of CBL derivate against
tumors with selective targeting of cancer cells. In addition, the
natural product of honokiol (HN), the novel potent chemo-preventive
or therapeutic entity/carrier, can target the mitochondria of cancer
cells through STAT3 to prevent cancer from spreading and metastasizing.
In this study, we designed and synthesized the honokiol–chlorambucil
(HN–CBL) co-prodrugs through carbonate ester linkage conjugating
with the targeted delivery help of the HN skeleton in cancer cells.
Biological evaluation indicated that HN–CBL can remarkably
enhance the antiproliferation of human leukemic cell lines CCRF-CEM,
Jurkat, U937, MV4-11, and K562. Furthermore, HN–CBL can also
selectively inhibit the lymphocytic leukemia (LL) cell survival compared
to those mononuclear cells derived from healthy donors (PBMCs), enhance
mitochondrial activity in leukemia cells, and induce LL cell
apoptosis. Molecular docking and western blot study showed that HN–CBL
can also bind with the STAT3 protein at some hydrophobic residues
and downregulate the phosphorylation level of STAT3-like HN. Significantly,
HN–CBL could dramatically delay leukemia growth in
vivo with no observable physiological toxicity. Thus, HN–CBL
may provide a novel and effective targeting therapeutic against LL
with fewer side effects.