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

Aneta Rogalska,Irena Oszczapowicz,Małgorzata Łukawska,Arkadiusz Gajek,Agnieszka Marczak,Aamir Ahmad

doi:10.1371/journal.pone.0201296

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.

Highlights

Anthracycline antibiotics are anti-neoplastic drugs that are effective against both hematological malignancies and solid tumors [1]
Our results clearly demonstrate that slightly basic compounds like DOX and DAU generate higher levels of ROS in SKOV-3 cells than their oxazoline derivatives (Fig 2A)
Our results clearly demonstrate that oxazolines are able to generate RNS in cancer cells derived from solid tumors

Summary

Introduction

Anthracycline antibiotics are anti-neoplastic drugs that are effective against both hematological malignancies and solid tumors [1]. The mechanisms of action of doxorubicin (DOX) and daunorubicin (DAU) have been associated with DNA damage, topoisomerase inhibition and reduction in the presence of free iron [2]. There is an urgent need for new approaches to anthracycline chemotherapy that could improve therapeutic index and overcome drug resistance, for example, by specific modification of parent drug structures. We modified DOX and DAU structures by creating an oxazoline ring at the daunosamine moiety through introduction of a NH2 group at the C-30 position of the daunosamine moiety.

Objectives

Methods

Results

Conclusion