Novel oxazolinoanthracyclines as tumor cell growth inhibitors—Contribution of autophagy and apoptosis in solid tumor cells death

Abstract

Chemical modification of known, effective drugs are one method to improve the chemotherapy of tumors. We reported ability of oxazoline analogs of doxorubicin (O-DOX) and daunorubicin (O-DAU) to induce apoptosis and autophagy in ovarian and liver cancer cells. Reactive oxygen and nitrogen species (ROS and RNS, respectively), together with intracellular calcium-mediated downstream signaling, are essential for the anticancer effect of these new anthracycline analogs. The changes of mitochondrial membrane potential and induction of the ceramide pathway suggests that these compounds induce cell death by apoptosis. In addition, a significant increase of autophagosome formation was observed by fluorescence assay and acridine orange staining, indicating that the new analogs also induce autophagic cell death. Compared to free DOX- and DAU-treated cells, we observed inhibition of colony formation and migration, a time-dependency between ROS/RNS levels and a greater fall in mitochondrial membrane potential. Altogether, our research broadens the base of molecular oxazolinoanthracyclines targets and reveals that derivatives mediated oxidative stress, ceramide production and increase in intracellular calcium level by mitochondria. Furthermore, our data highlight the importance of mitochondria that simultaneously assume the role of activator of autophagy and apoptosis signals.

Doxorubicin-Induced Cancer Cell Senescence Shows a Time Delay Effect and Is Inhibited by Epithelial-Mesenchymal Transition (EMT)

“…Doxorubicin is a commonly used chemotherapy drug that can induce DNA cross-linking and lead to cell apoptosis, autophagy, and/or senescence [21–23]. Unlike apoptosis, senescence is a relatively stable state with active metabolism.…”

Tioconazole and Chloroquine Act Synergistically to Combat Doxorubicin-Induced Toxicity via Inactivation of PI3K/AKT/mTOR Signaling Mediated ROS-Dependent Apoptosis and Autophagic Flux Inhibition in MCF-7 Breast Cancer Cells

“…The autophagosome level of MCF-7 treated cells, and isolated tumor cells of the mammary gland [ 97 ] were analyzed by flow cytometry using a proprietary fluorescent autophagosome marker (lex = 333/lem = 518 nm) of autophagy assay kit (#MAK138S, Sigma Aldrich, St. Louis, MO, USA) and analysis was performed following manufacturer protocol [ 98 ]. Briefly, treated cells were washed with ice-cold PBS twice.…”

Antileukemic activity of novel adenosine derivatives

“…Incubation with drugs was performed for different times (2–48 h). The medium was then removed, and the cells were washed with phosphate buffered saline (PBS) 35,36 . Finally, a dye loading solution (Fluo-4 NW dye, probenecid, assay buffer—1xHBSS, 20 mM HEPES; 100 μL per well) was processed according to the Fluo-4 NW Calcium Assay Kit protocol (Molecular Probes) and incubated for 30 min in the dark at 37 °C, and then for another 30 min at the room temperature.…”