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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.

ABSTRACT: The 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.

SUBMITTER: Xia L

PROVIDER: S-EPMC7424726 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Honokiol-Chlorambucil Co-Prodrugs Selectively Enhance the Killing Effect through STAT3 Binding on Lymphocytic Leukemia Cells <i>In Vitro</i> and <i>In Vivo</i>.

Xia Li L Kang Dali D Wan Dan D Chu Chu C Chen Meizi M Zhang Shuihan S Li Xiong X He Leye L Yan Jianye J Liu Teng T Peng Yongbo Y

ACS omega 20200729 31

The 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 pre ...[more]

PMID: 32803080

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Project description:IntroductionIbrutinib (ibr) monotherapy and the combination of obinutuzumab plus chlorambucil (obi) are approved for previously untreated chronic lymphocytic leukemia (CLL). No trials directly comparing their efficacy are available. Therefore a matching-adjusted indirect comparison (MAIC) was performed to provide insight into their relative efficacy in terms of progression-free survival (PFS) and overall survival (OS). MAIC attempts to adjust for between-trial differences in factors known or suspected to influence treatment effects, to minimize bias.MethodsA MAIC within a Bayesian framework was conducted using individual patient data from the RESONATE-2 study of ibr versus chlorambucil and published data from the CLL11 study of obi versus chlorambucil. Both studies were conducted in patients ineligible for full-dose fludarabine-based therapy. After matching, the reweighted adjusted relative efficacy measure of ibr versus chlorambucil from RESONATE-2 [hazard ratio (HR), 95% credible interval (CrI)] was compared with that of obi versus chlorambucil from CLL11 for each endpoint, using a Bayesian indirect comparison.ResultsOur results suggest that in a population with similar average baseline characteristics to CLL11, ibr would improve PFS and OS outcomes compared to obi. Before matching, the HRs for ibr versus obi were 0.48 [CrI = 0.22-1.02, p(HR <1) = 97%], 0.85 [CrI = 0.44-1.63, p(HR <1) = 69%], and 0.40 [CrI = 0.10-1.54, p(HR <1) = 91%] for PFS by investigator assessment, PFS by independent review committee, and OS, respectively. After matching on all available characteristics the HRs decreased to 0.12 [CrI = 0.02-0.97, p(HR <1) = 98%], 0.24 [CrI = 0.04-1.35, p(HR <1) = 95%], and 0.21 [CrI = <0.01-8.89, p(HR <1) = 79%], respectively. There was a large variance around the treatment effect for OS due to the low number of deaths.ConclusionOur analysis suggests that ibrutinib is highly likely to provide greater PFS benefit than obinutuzumab plus chlorambucil in older or less fit patients with previously untreated CLL. There is also an indication of improvement in OS, albeit with a higher uncertainty due to the low number of events.FundingJanssen-Cilag Ltd.

Dataset Information

Honokiol-Chlorambucil Co-Prodrugs Selectively Enhance the Killing Effect through STAT3 Binding on Lymphocytic Leukemia Cells In Vitro and In Vivo.

Publications

Honokiol-Chlorambucil Co-Prodrugs Selectively Enhance the Killing Effect through STAT3 Binding on Lymphocytic Leukemia Cells <i>In Vitro</i> and <i>In Vivo</i>.

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