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Hydroxamic acid group is one of the characteristic pharmacophores of histone deacetylase (HDAC) inhibitors. But here, we discovered a series of hydroxamic acid-based microtubule destabilizing agents (MDAs), which were derived from shortening the length of the linker in HDAC6 inhibitor SKLB-23bb. Interestingly, the low nanomolar antiproliferative activity of these MDAs depended on the presence of hydroxamic acid groups, but their inhibitory effects on HDAC were lost. Among them, 12b showed favorable metabolism stability, high bioavailability, and potent antitumor activity in multidrug-resistant cell lines and A2780/T xenograft model. More importantly, in the patient-derived xenograft models of triple-negative breast cancer and osimertinib-resistant non-small-cell lung cancer, both 20 mg/kg oral and 10 mg/kg intravenous administration of 12b could induce more than 70% tumor inhibition without obvious toxicity. Overall, we discovered that 12b, as a novel MDA based on hydroxamic acid, could serve as a potential MDA for further investigation.

Background: PEGylation of stealth liposomes elevates their stability and prolongs plasma half-life. Stealth liposomes modified with targeting ligands are expected to be ideal drug delivery carriers. Objective: To encapsulate docetaxel in tbFGF (truncated basic fibroblast growth factor)-functionalized liposomes with mPEG2000-VE (d-α-tocopheryl polyethylene glycol succinate, TPGS2K) and measure their antitumor effects in vitro and in vivo. Methods: TPGS2K and COOH-PEG2000-VE were synthesized, and tbFGF was conjugated to COOH-PEG2000-VE to prepare tbFGF-PEG2000-VE. Then, tbFGF-functionalized liposomes (DTX-tbFGF-LPs) were prepared by inserting tbFGF-PEG2000-VE into docetaxel liposomes comprising TPGS2K (DTX-PEG-LPs). The stabilities and drug release profiles of the formulation were evaluated. P-glycoprotein (P-gp) inhibition was measured by ATPase assay. MTT and cell uptake were measured with B16 cells. A B16 C57BL/6 mouse model was used to evaluate in vivo antitumor efficacy. Results: Both DTX-PEG-LPs and DTX-tbFGF-LPs exhibited good stability and sustained drug release. MTT, flow cytometry, and fluorescence microscopy of B16 cells revealed higher antitumor activity and more efficient cell uptake for DTX-tbFGF-LPs compared with DTX-PEG-LPs and DTX-LPs. The P-gp ATPase assay showed that both PEG-LP and tbFGF-PEG-LP formulations inhibited P-gp pump activity in vitro. DTX-tbFGF-LPs had the highest antitumor efficacy and lowest toxicity in vivo. Conclusion: Truncated basic fibroblast growth factor-functionalized liposomes with TPGS2K as drug delivery nanocarriers were effective chemotherapy agents targeting FGFR-overexpressing tumors.

β-Elemene is a volatile oil used for the treatment of cancer, but poor solubility, low bioavailability, and various adverse reactions limit its application. For ameliorating risks of the venous toxicity of β-elemene, intravenously injectable micelle of β-elemene was prepared using the thin-film hydration method. The results pointed out the micelles were uniformly spherical with about 20.96 ± 0.1966 nm in average diameter and exhibited high entrapment efficiency (99.02% ± 0.88%). As revealed by drug release studies in vitro, β-elemene micelles had sustained drug release. Compared with free β-elemene, the micelles increased the drug cellular uptake and enhanced the anti-tumor effect in vitro through retarding cell cycle and inducing apoptosis. Meanwhile, the elevated serum stability of β-elemene micelles implied less drug leakage and reduced toxicity. The wound healing and tube formation assay in vitro demonstrated the anti-metastasis and anti-angiogenesis effects of β-elemene micelles. Moreover, the pharmacokinetics study showed the AUC and T1/2 of β-elemene in micelle group were 1.79 and 1.62 times of that in free β-elemene group, suggesting the circulation time of β-elemene in the blood had been prolonged. In addition, β-elemene micelles showed a favorable antitumor response compared with the β-elemene solution on C26 colon cancer-bearing mice model. Local irritation study investigated in rabbits indicated that the β-elemene micelles strikingly mitigated the irritation to the injection sites compared with free β-elemene. These results proved that the micelle could be a good candidate as an auspicious drug delivery system of β-elemene for the prospective clinical treatment of carcinoma.

Searching the targets of natural products is very important for drug discovery and elucidating the mechanism of drug action and disease. Honokiol (HK), as the major active component of Magnolia officinalis RehderE.H.Wilson, has been widely used in medicine and cosmetics. Among its bioactivities, its anti-inflammatory activity is particularly impressive. However, the target protein of HK in anti-inflammatory action and its regulatory mechanism are unclear.Here, we identified the target protein and molecular mechanism of the anti- inflammatory action of HK.First, an LPS-induced septic shock model and DSS-induced ulcerative colitis model were used to assess the anti-inflammatory efficacy of HK. Second, the drug affinity responsive target stability, proteomics analysis, thermal shift assays and cellular thermal shift assays were used to identify and validate the target of HK. Finally, western blot, ELISA, LDH immunofluorescence staining, shRNA and LC/MS for L-leucine analysis were performed to determine the mechanism of the anti-inflammatory action of HK.This study revealed that HK significantly alleviated LPS-induced septic shock and DSS-induced ulcerative colitis in vivo, suggesting that HK has significant anti-inflammatory activity. HK treatment dramatically reduced IL-1β release and caspase-1 activation at different time points, showing that HK could inhibit both NLRP3 inflammasome priming and activation processes in cells. HK also suppressed adaptor apoptosis speck-like protein oligomerization. Mechanistically, SLC3A2 was identified as a direct target of HK in THP-1 cells. HK downregulated SLC3A2 expression by promoting its degradation via proteasome-mediated proteolysis. Further study demonstrated that HK triggered SLC3A2 to suppress NLRP3 inflammasome activation by significantly reducing the content of L-leucine transported into cells and lysosomes to block the mTORC1 pathway.Our work identified HK as a promising anti-inflammatory drug candidate through the SLC3A2/L-leucine/mTORC1/NLRP3 pathways.

Post-myocardial infarction heart failure (post-MI HF) is one of the leading global causes of death, and current prevention and treatment methods still cannot avoid the increasing incidence. Honokiol (HK) has previously been reported to improve myocardial ischemia/reperfusion injury and reverse myocardial hypertrophy by activating Sirt1 and Sirt3. We suspect that HK may also have a therapeutic effect on post-MI HF. In this study, we aimed to investigate the efficacy and mechanism of HK in the treatment of post-MI HF. We found that HK inhibited myocardial reactive oxygen species (ROS) production, reduced myocardial fibrosis, and improved cardiac function in mice after MI. HK also reduced the abnormality of mitochondrial membrane potential (MMP) and apoptosis of cardiomyocytes caused by peroxide in neonatal cardiomyocytes. RNAseq results revealed that HK restored the transcriptome changes to a certain extent and significantly enhanced the expression of mitochondrial inner membrane uncoupling protein isoform 3 (Ucp3), a protein that inhibits the production of mitochondrial ROS, protects cardiomyocytes, and relieves heart failure after myocardial infarction (MI). In cardiomyocytes with impaired Ucp3 expression, HK cannot protect against the damage caused by peroxide. More importantly, in Ucp3 knockout mice, HK did not change the increase in the ROS level and cardiac function damage after MI. Taken together, our results suggest that HK can increase the expression of the cardioprotective protein Ucp3 and maintain MMP, thereby inhibiting the production of ROS after MI and ameliorating heart failure.