ABSTRACT
Multiple myeloma (MM) is a common malignant hematologic neoplasm, and the involvement of epigenetic modifications in its development and drug resistance has received widespread attention. Ferroptosis, a new ferroptosis-dependent programmed death mode, is closely associated with the development of MM. The novel methyltransferase inhibitor DCG066 has higher cell activity, but its mechanism of action in MM has not been clarified. Here, we found that DCG066 (5µM) inhibited the proliferation and induced ferroptosis in MM cells; the intracellular levels of ROS, iron, and MDA were significantly elevated, and the level of GSH was reduced after the treatment of DCG066; The protein expression levels of SLC7A11, GPX4, Nrf2 and HO-1 were significantly reduced, and these phenomena could be reversed by ferroptosis inhibitor Ferrostatin-1 (Fer-1) and Nrf2 activator Tert-butyl hydroquinone (TBHQ). Meanwhile, the protein expression levels of Keap1 was increased, and heat shock proteins (HSP70, HSP90 and HSPB1) were reduced after DCG066 treatment. In conclusion, this study confirmed that DCG066 inhibits MM proliferation and induces ferroptosis via the Nrf2/HO-1 pathway.
Subject(s)
Ferroptosis , Heme Oxygenase-1 , Multiple Myeloma , NF-E2-Related Factor 2 , Signal Transduction , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Multiple Myeloma/metabolism , Ferroptosis/drug effects , Humans , NF-E2-Related Factor 2/metabolism , Heme Oxygenase-1/metabolism , Heme Oxygenase-1/genetics , Cell Line, Tumor , Signal Transduction/drug effects , Histone-Lysine N-Methyltransferase/metabolism , Histone-Lysine N-Methyltransferase/antagonists & inhibitors , Histone-Lysine N-Methyltransferase/genetics , Cell Proliferation/drug effects , Enzyme Inhibitors/pharmacology , Neoplasm Proteins/metabolism , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Histocompatibility AntigensABSTRACT
TiO2 and SiO2 are very useful materials for building biointerfaces. A particularly interesting aspect is their interaction with lipid bilayers. Many past research efforts focused on phosphocholine (PC) lipids, which form supported lipid bilayers (SLB) on SiO2 at physiological conditions but are adsorbed as intact liposomes on TiO2. Low pH was required to form PC SLBs on TiO2. This work intends to understand the surface forces and chemistry responsible for such differences. Two charge neutral lipids: 1,2-dioleoyl- sn-glycero-3-phosphocholine (DOPC) and 2-((2,3-bis(oleoyloxy)propyl)dimethylammonio)ethyl ethyl phosphate (DOCPe) and two negatively charged lipids: 1,2-dioleoyl- sn-glycero-3-phospho-l-serine (DOPS) and 2-((2,3-bis(oleoyloxy)propyl)dimethylammonio)ethyl hydrogen phosphate (DOCP) were used. Using calcein leakage assays, adsorption measurement, cryo-TEM, and washing, we concluded that charge is the dominating factor on SiO2. The two neutral lipids form SLB on SiO2 at pH 3 and 7, but the two negatively charged ones cannot form. On TiO2, both charge and coordination chemistry are important. The two anionic lipids formed SLB from pH 3 to 10. DOCP had stronger affinity than DOPS likely due to the tighter terminal phosphate binding of the former. The two neutral liposomes formed SLB only at pH 3, where phosphate interaction and van der Waals force are deemed important. The pH 3 prepared TiO2 DOPC SLBs are destabilized at neutral pH, indicating the reversible nature of the interaction. This work has provided new insights into two important materials interacting with common liposomes, which are important for reproducible biosensing, device fabrication, and drug delivery applications.
