Injectable (−)-gossypol-loaded Pluronic P85 micelles for cancer chemoradiotherapy

Tomoda, Keishiro; Chiang, Hsüch‐Ching; Kozak, Kevin R.; Kwon, Glen S.

doi:10.1080/09553002.2016.1257833

Cited by 9 publications

(3 citation statements)

References 25 publications

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“…Thus gossypol also has been developed for anticarcinogen, male contraceptive and female hormone-dependent cell proliferation diseases [ 30 ]. Because of its anti-tumor application prospects, the current studies of cytotoxic mechanism of gossypol and its derivatives based on tumor cells [ 31 ]. Few studies have addressed the specific molecular mechanisms of gossypol damage to spermatogonia, however, most studies on reproductive toxicity of gossypol still major concerned in its toxic phenomenon [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

The aldehyde group of gossypol induces mitochondrial apoptosis via ROS-SIRT1-p53-PUMA pathway in male germline stem cell

Cui

et al. 2017

Oncotarget

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As a widely grown economic crop, cotton is the major oil and protein resource for human and livestock. But the highly toxic of gossypol in cottonseed severely restricts its effective utilization, consequently creating huge resource waste. Previous studies have shown the male germline stem cells were the most vulnerable cells in gossypol damages, but the mechanism was still unclear. We found gossypol induced cell viability decline resulted from apoptosis. And the increase of Caspase-9 activity in gossypol treatment hinted the mitochondrial apoptosis. So the mitochondrial dysfunction was confirmed by the decreased mitochondrial membrane potential and ATP concentration. We found the higher intracellular H2O2 level did not accompany with the O2·- associated increase in gossypol-treated, which indicated that gossypol obstructed the intracellular reactive oxygen species (ROS) elimination. Manipulated gossypol-induced H2O2 level by H2O2 and α-lipoic acid, we demonstrated that the mitochondrial dysfunction resulted from the excessive intracellular H2O2. Treated with Apogossypolone (ApoG2), an aldehyde group removed derivative of gossypol, the GSH/GSSG ratio and H2O2 did not decrease. ApoG2 also did not cause the mitochondrial apoptosis. So the aldehyde group is key factor in gossypol cytotoxicity. We respectively detected the NAD+/NADH ratio, SIRT1 activity, the relative protein level and apoptosis. Comparing with the specific inhibitors groups, the data illustrated that gossypol induced apoptosis through SIRT1-P53-PUMA pathway. This study helped to overcome barriers of gossypol cytotoxicity, which is crucial in feed and food use of cottonseed. This also provides a reference for the gossypol derivatives using in male contraception and anticancer.

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Section: Discussionmentioning

confidence: 99%

The aldehyde group of gossypol induces mitochondrial apoptosis via ROS-SIRT1-p53-PUMA pathway in male germline stem cell

Cui

et al. 2017

Oncotarget

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“…However, such an approach does come with limitations that cannot go ignored, due to potentially diminished availability of the helical peptide therapeutic moiety, through masking and immunogenic effects from PEG, or limitations in peptide cargo lengths of 17–36 aa [ 501 , 502 ]. Nevertheless, as a way of highlighting the potential of this approach, Gossypol loaded micelles combined with A549 cells and radiation therapy in a xenograft mouse model [ 503 ], showed 7x greater efficacy against tumors than Gossypol alone [ 504 ]. Moreover, biomimetic poly(lactic-coglycolic acid) (PLGA) combined with red blood-cell membrane (RBCm) as nanoparticles loaded with Obatoclax mesylate for the treatment of non-small-cell lung cancer, also showed significant success in prolonging drug circulation in the presence of a reduced immune response against the particles [ 505 ].…”

Section: Main Textmentioning

confidence: 99%

BH3-mimetics: recent developments in cancer therapy

Townsend

Kozhevnikova

Cexus

et al. 2021

J Exp Clin Cancer Res

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The hopeful outcomes from 30 years of research in BH3-mimetics have indeed served a number of solid paradigms for targeting intermediates from the apoptosis pathway in a variety of diseased states. Not only have such rational approaches in drug design yielded several key therapeutics, such outputs have also offered insights into the integrated mechanistic aspects of basic and clinical research at the genetics level for the future. In no other area of medical research have the effects of such work been felt, than in cancer research, through targeting the BAX-Bcl-2 protein-protein interactions. With these promising outputs in mind, several mimetics, and their potential therapeutic applications, have also been developed for several other pathological conditions, such as cardiovascular disease and tissue fibrosis, thus highlighting the universal importance of the intrinsic arm of the apoptosis pathway and its input to general tissue homeostasis. Considering such recent developments, and in a field that has generated so much scientific interest, we take stock of how the broadening area of BH3-mimetics has developed and diversified, with a focus on their uses in single and combined cancer treatment regimens and recently explored therapeutic delivery methods that may aid the development of future therapeutics of this nature.

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“…Tomoda et al reported an injectable (-)-gossypol-loaded Pluronic P85 micelle which had limited antitumor efficacy alone but could significantly enhance the antitumor efficacy of radiation therapy. 22 Earlier, Li et al reported liposomes that encapsulated (-)-gossypol-enriched cottonseed oil. 23 However, the cottonseed oil contained a mixture of (-)-gossypol (65%) and (+)-gossypol (35%) rather than a single-isomer drug.…”

Section: Introductionmentioning

confidence: 99%

Cyclic RGD-Decorated Liposomal Gossypol AT-101 Targeting for Enhanced Antitumor Effect

Liu¹,

Zhang²,

Zhang³

et al. 2022

IJN

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Introduction (-)-Gossypol (AT-101), the (-)-enantiomer of the natural compound gossypol, has shown significant inhibitory effects on various types of cancers such as osteosarcoma, myeloma, glioma, lung cancer, and prostate cancer. However, the clinical application of (-)-gossypol was often hindered by its evident side effects and the low bioavailability via oral administration, which necessitated the development of suitable (-)-gossypol preparations to settle the problems. In this study, injectable cyclic RGD (cRGD)-decorated liposome (cRGD-LP) was prepared for tumor-targeted delivery of (-)-gossypol. Methods The cRGD-LP was prepared based on cRGD-modified lipids. For comparison, a non-cRGD-containing liposome (LP) with a similar chemical composition to cRGD-LP was specially designed. The physicochemical properties of (-)-gossypol-loaded cRGD-LP (Gos/cRGD-LP) were investigated in terms of the drug loading efficiency, particle size, morphology, drug release, and so on. The inhibitory effect of Gos/cRGD-LP on the proliferation of tumor cells in vitro was evaluated using different cell lines. The biodistribution of cRGD-LP in vivo was investigated via the near-infrared (NIR) fluorescence imaging technique. The antitumor effect of Gos/cRGD-LP in vivo was evaluated in PC-3 tumor-bearing nude mice. Results Gos/cRGD-LP had an average particle size of about 62 nm with a narrow size distribution, drug loading efficiency of over 90%, and sustained drug release for over 96 h. The results of NIR fluorescence imaging demonstrated the enhanced tumor targeting of cRGD-LP in vivo. Moreover, Gos/cRGD-LP showed a significantly enhanced inhibitory effect on PC-3 tumors in mice, with a tumor inhibition rate of over 74% and good biocompatibility. Conclusion The incorporation of cRGD could significantly enhance the tumor-targeting effect of the liposomes and improve the antitumor effect of the liposomal (-)-gossypol in vivo, which indicated the potential of Gos/cRGD-LP that warrants further investigation for clinical applications of this single-isomer drug.

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Injectable (−)-gossypol-loaded Pluronic P85 micelles for cancer chemoradiotherapy

Cited by 9 publications

References 25 publications

The aldehyde group of gossypol induces mitochondrial apoptosis via ROS-SIRT1-p53-PUMA pathway in male germline stem cell

The aldehyde group of gossypol induces mitochondrial apoptosis via ROS-SIRT1-p53-PUMA pathway in male germline stem cell

BH3-mimetics: recent developments in cancer therapy

Cyclic RGD-Decorated Liposomal Gossypol AT-101 Targeting for Enhanced Antitumor Effect

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