GPX4 inhibition synergistically boosts mitochondria targeting nanoartemisinin-induced apoptosis/ferroptosis combination cancer therapy

Abstract

Artemisinin, originally discovered for antimalaria, has received much attention in recent cancer therapy. The anticancer mechanisms of artemisinin are complicated and debatable. It also remains challenges in the delivery of...

Liensinine Inhibits Mitophagy to Potentiate Mitochondria-Targeting Artemisinin-Loaded Polymer Nanostructures for Breast Cancer Therapy

“…51,52 In comparison to untreated MCF-7 cells, the P62 level of the cells treated with Lien or the ART/Lien combination significantly increased, while P62 decreased when the cells were treated with ART (Figure 5C). As we previously reported, 23 cytotoxic R • or ROS generated from ART should induce the upregulation of P62 in the cells, similar to that observed in the case of Lien treatment. The decrease of P62 in ART-treated cells suggests the occurrence of mitophagy and the degradation of generated P62 in the mitolysosome system.…”

“…24 h treatment further increased intracellular ROS levels. As we previously reported, mitochondrial heme of MCF-7 cells activated ART to generate alkyl radicals and further converted into other ROS, such as alkoxyl radicals (RO • ). When the cells were incubated with the ART/Lien combination for either 12 or 24 h, stronger ROS-derived green fluorescence was detected than that in ART-alone-incubated cells.…”

“…Mitochondria-targeting nanomedicines were prepared from PLGA, C 18 -PEG 2000 -TPP (CPT), and DLPE-S-S-mPEG 4000 (DSSP), according to our previous study report . The synthesis and 1 H NMR of CPT and DSSP are displayed in Scheme S1 and Figures S1 and S2.…”

“…Unfortunately, raw ART or particulate ART using conventional nanocarrier delivery to the cytoplasm only achieved limited success in cancer therapy due to the low concentration of heme in the cytoplasm of cancer cells , Since fresh heme is produced in mitochondria, the mitochondrion is thought to be a more ideal therapeutic target for ART in cancer treatment due to the higher concentration of heme in the mitochondrion than that in the cytoplasm . Actually, mitochondria-targeting TPP–artemisinin and coumarin–artemisinin conjugates show a significantly higher ability to inhibit cancer cell growth than artemisinin. , Alternatively, we have previously developed a mitochondria-targeting nanocarrier to deliver artemisinin and improve anticancer activity . Although the IC 50 values of the mitochondria-targeting artemisinin nanomedicine to various cancer cell lines (∼0.4 μg/mL) are at least 100-fold lower than that of free artemisinin (>50 μg/mL), a small part of cancer cells remain alive, even increasing the drug concentration.…”

“…21,22 Alternatively, we have previously developed a mitochondria-targeting nanocarrier to deliver artemisinin and improve anticancer activity. 23 Although the IC 50 values of the mitochondria-targeting artemisinin nanomedicine to various cancer cell lines (∼0.4 μg/mL) are at least 100-fold lower than that of free artemisinin (>50 μg/mL), a small part of cancer cells remain alive, even increasing the drug concentration. For example, 20−30% of MCF-7 cells cannot be killed even when the concentration of the mitochondria-targeting artemisinin nanomedicine is up to 10 μg/mL, which is different from other conventional chemotherapeutics.…”