Ursolic acid (UA) is a food-plant-derived natural product which has good anticancer activities and low toxicity. However, the poor water solubility of UA limits its application in clinic. To address this issue, we developed a carrier-free nanodrug by self-assembly of UA. Here, we showed that UA nanoparticles (NPs) have a near-spherical shape with a diameter of ∼150 nm. UA NPs exhibited higher antiproliferative activity; significantly caused apoptosis; decreased the expression of COX-2/VEGFR2/VEGFA; and increased the immunostimulatory activity of TNF-α, IL-6, and IFN-β and decreased the activity of STAT-3 in A549 cells in vitro. Furthermore, UA NPs could inhibit tumor growth and have the ability of liver protection in vivo. More importantly, UA NPs could significantly improve the activation of CD4+ T-cells, which indicated that UA NPs have the potential for immunotherapy. Overall, a carrier-free UA nanodrug may be a promising drug to further enhance their anticancer efficacy and immune function.
A targeting drug delivery system (TDDS) can selectively deliver antitumor drugs to cancerous parts to improve its anticancer efficacy. Hence, a targeted drug delivery system (UA/siVEGF@MSN-FA) coloading ursolic acid (UA) and vascular endothelial growth factor (VEGF) targeted siRNA (siVEGF) based on mesoporous silica (MSN) nanocarrier modified by a folic acid (FA) molecule was designed and synthesized. The MSN-FA nanoparticles were investigated for shape, diameter, and zeta potential and and by infrared (IR) spectroscopy. FR-overexpressing HeLa cells and FR-negative HepG2 cell lines were used to evaluate the in vitro cellular uptake and the cytotoxicity of MSN-FA nanoparticles. The morphology of HeLa cells transfected with siVEGF@MSN-FA was observed using fluorescence microscopy. Our findings demonstrated that UA@MSN-FA nanoparticles were near-spherical, and the particle size was about 209 ± 9.21 nm. The MSN-FA nanocarrier not only could enhance the in vitro transfection efficiency and the stability of siVEGF but also could further improve the targeted anticancer efficacy of UA and siVEGF via the active targeting property of FA. Overall, the MSN-FA drug delivery system could serve as an excellent material in biomedical applications.
In recent years, phase separation has been increasingly reported to play a pivotal role in a wide range of biological processes. Due to the close relationships between cancer and disorders in intracellular physiological function, the identification of new mechanisms involved in intracellular regulation has been regarded as a new direction for cancer therapy. Introducing the concept of phase separation into complex descriptions of disease mechanisms may provide many different insights. Here, we review the recent findings on the phase separation of cancer‐related proteins, describing the possible relationships between phase separation and key proteins associated with cancer and indicate possible regulatory modalities, especially drug candidates for phase separation, which may provide more effective strategies for cancer therapy.
Acute myeloid leukemia (AML) is an aggressive hematological malignancy. Nearly 50% of patients who receive the most intensive treatment inevitably suffer disease relapse, likely resulting from the persistence of drug‑resistant leukemia stem cells (LSCs). AML cells especially LSCs are highly dependent on mitochondrial oxidative phosphorylation (OXPHOS) for survival, but the mechanism involved in OXPHOS hyperactivity is unclear and a noncytotoxic strategy to inhibit OXPHOS is lacking. Here, we demonstrate for the first time that ZDHHC21 palmitoyltransferase serves as a key regulator of OXPHOS hyperactivity in AML cells. The depletion/inhibition of ZDHHC21 effectively induced myeloid differentiation and weakened stemness potential by inhibiting OXPHOS in AML cells. Interestingly, FLT3-ITD mutated AML cells expressed significantly higher levels of ZDHHC21 and exhibited better sensitivity to ZDHHC21 inhibition. Mechanistically, ZDHHC21 specifically catalyzed the palmitoylation of mitochondrial kinase AK2 and further activated OXPHOS in leukemic blasts. Inhibition of ZDHHC21 arrested the in vivo growth of AML cells and extended the survival of mice inoculated with AML cell lines and PDX-AML blasts. Moreover, targeting ZDHHC21 to suppress OXPHOS markedly eradicated AML blasts and enhanced chemotherapy efficacy in relapsed/refractory leukemia. Together, these findings not only uncover a new biological function of palmitoyltransferase ZDHHC21 in regulating AML oxidative phosphorylation, but also indicate that ZDHHC21 inhibition is a promising therapeutic regimen for patients with AML, especially relapsed/refractory leukemia.
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