Synthetic Makaluvamine Analogs Decrease c-Kit Expression and Are Cytotoxic to Neuroendocrine Tumor Cells

Zviadi Aburjania; Jason D. Whitt; Samuel Jang; Dwayaja H. Nadkarni; Herbert Chen; J. Bart Rose; Sadanandan E. Velu; Renata Jaskula-Sztul

doi:10.3390/molecules25214940

Molecules (Oct 2020)

Synthetic Makaluvamine Analogs Decrease c-Kit Expression and Are Cytotoxic to Neuroendocrine Tumor Cells

Zviadi Aburjania,
Jason D. Whitt,
Samuel Jang,
Dwayaja H. Nadkarni,
Herbert Chen,
J. Bart Rose,
Sadanandan E. Velu,
Renata Jaskula-Sztul

Affiliations

Zviadi Aburjania: Department of Surgery, University of Alabama at Birmingham, 1824 6th Avenue S., Birmingham, AL 35233, USA
Jason D. Whitt: Department of Surgery, University of Alabama at Birmingham, 1824 6th Avenue S., Birmingham, AL 35233, USA
Samuel Jang: Department of Surgery, University of Alabama at Birmingham, 1824 6th Avenue S., Birmingham, AL 35233, USA
Dwayaja H. Nadkarni: Department of Chemistry, University of Alabama at Birmingham, 901 14th Street S., Birmingham, AL 35294, USA
Herbert Chen: Department of Surgery, University of Alabama at Birmingham, 1824 6th Avenue S., Birmingham, AL 35233, USA
J. Bart Rose: Department of Surgery, University of Alabama at Birmingham, 1824 6th Avenue S., Birmingham, AL 35233, USA
Sadanandan E. Velu: Department of Chemistry, University of Alabama at Birmingham, 901 14th Street S., Birmingham, AL 35294, USA
Renata Jaskula-Sztul: Department of Surgery, University of Alabama at Birmingham, 1824 6th Avenue S., Birmingham, AL 35233, USA

DOI: https://doi.org/10.3390/molecules25214940
Journal volume & issue: Vol. 25, no. 21
p. 4940

Abstract

Read online

In an effort to discover viable systemic chemotherapeutic agents for neuroendocrine tumors (NETs), we screened a small library of 18 drug-like compounds obtained from the Velu lab against pulmonary (H727) and thyroid (MZ-CRC-1 and TT) neuroendocrine tumor-derived cell lines. Two potent lead compounds (DHN-II-84 and DHN-III-14) identified from this screening were found to be analogs of the natural product makaluvamine. We further characterized the antitumor activities of these two compounds using pulmonary (H727), thyroid (MZ-CRC-1) and pancreatic (BON) neuroendocrine tumor cell lines. Flow cytometry showed a dose-dependent increase in apoptosis in all cell lines. Induction of apoptosis with these compounds was also supported by the decrease in myeloid cell leukemia-1 (MCL-1) and X-chromosome linked inhibitor of apoptosis (XIAP) detected by Western blot. Compound treatment decreased NET markers chromogranin A (CgA) and achaete-scute homolog 1 (ASCL1) in a dose-dependent manner. Moreover, the gene expression analysis showed that the compound treatment reduced c-Kit proto-oncogene expression in the NET cell lines. Induction of apoptosis could also have been caused by the inhibition of c-Kit expression, in addition to the known mechanisms such as damage of DNA by topoisomerase II inhibition for this class of compounds. In summary, makaluvamine analogs DHN-II-84 and DHN-III-14 induced apoptosis, decreased neuroendocrine tumor markers, and showed promising antitumor activity in pulmonary, thyroid, and pancreatic NET cell lines, and hold potential to be developed as an effective treatment to combat neuroendocrine tumors.

Published in Molecules

ISSN: 1420-3049 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Chemistry: Organic chemistry
Website: http://www.mdpi.com/journal/molecules

About the journal

Abstract

Keywords