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Title: The nuclear membrane as a barrier to the action of anthracycline chemotherapeutics

Gulnihal Ozcan

Koc University, Turkey

Biography

Dr. Ozcan received her MD degree at Hacettepe University School of Medicine in 2007. She completed her residency in Pharmacology at Ankara University School of Medicine in 2011 and investigated signaling mechanisms of G-protein coupled receptors. After residency, she was employed in the Ministry of Health, Turkish Medicines and Medical Devices Agency in the context of public service responsibility.  She conducted her post-doctoral studies at University of Texas MD Anderson Cancer Center, Department of Experimental Therapeutics. Since 2016, she has been investigating the mechanisms of chemoresistance in gastric cancer and ovarian cancer at Koc University Research Center for Translational Medicine.

Abstract

Anthracyclines are one of the most commonly used and most effective chemotherapeutic agents in a wide variety of cancers. Their primary mechanism of action is through binding to DNA, which leads to inhibition of DNA synthesis, DNA damage and eventually apoptosis. Since they act primarily by binding to DNA, the intra-nuclear concentration of these chemotherapeutics is a major determinant of the drug efficacy. Studies suggest that anthracyclines can enter the nucleus through both passive diffusion and an energy-dependent transport via nuclear pore complex (NPC). In sensitive cells, they have a tendency to accumulate within the nucleus. However, in chemoresistant cancer cells, anthracyclines cannot accumulate in the nucleus despite the presence of the drug within the cytoplasm. This phenomenon is known as nuclear sparing phenomenon and is thought to be an important mechanism for anthracycline resistance. Moreover, the nuclear barriers that lead to the nuclear sparing may limit the efficacy of the nanocarriers designed to overcome only the cytoplasmic membrane barriers for anthracyclines.  Therefore, uncovering the molecular mechanisms of nuclear sparing is of substantial importance. The efflux pumps that were recently shown to be localized in the nuclear membrane are strong candidate proteins to explain nuclear sparing in chemoresistance cancer cells. Our studies also suggest that, an NPC protein may have an important role in controlling the active transport of anthracyclines between the cytoplasm and the nucleus. Here, we will discuss the role of nuclear efflux pumps and NPC proteins in nuclear-sparing phenomenon together with the strategies to design new carriers that can overcome the nuclear barriers against anthracycline action.
Audience take away:
• The role of nuclear sparing phenomenon in chemoresistance to anthracycline chemotherapeutics,
• Underlying mechanisms of nuclear sparing,
• Strategies to overcome nuclear barriers.
The findings of the study will assist the design of drug carriers that could overcome nuclear barriers against the action of anthracycline chemotherapeutics.