Anti-Leukemic Properties of Aplysinopsin Derivative EE-84 Alone and Combined to BH3 Mimetic A-1210477.

Abstract

Aplysinopsins are a class of marine indole alkaloids that exhibit a wide range of biological activities. Although both the indole and N-benzyl moieties of aplysinopsins are known to possess antiproliferative activity against cancer cells, their mechanism of action remains unclear. Through in vitro and in vivo proliferation and viability screening of newly synthesized aplysinopsin analogs on myelogenous leukemia cell lines and zebrafish toxicity tests, as well as analysis of differential toxicity in noncancerous RPMI 1788 cells and PBMCs, we identified EE-84 as a promising novel drug candidate against chronic myeloid leukemia. This indole derivative demonstrated drug-likeness in agreement with Lipinski's rule of five. Furthermore, EE-84 induced a senescent-like phenotype in K562 cells in line with its cytostatic effect. EE-84-treated K562 cells underwent morphological changes in line with mitochondrial dysfunction concomitant with autophagy and ER stress induction. Finally, we demonstrated the synergistic cytotoxic effect of EE-84 with a BH3 mimetic, the Mcl-1 inhibitor A-1210477, against imatinib-sensitive and resistant K562 cells, highlighting the inhibition of antiapoptotic Bcl-2 proteins as a promising novel senolytic approach against chronic myeloid leukemia.

• Authors: Sungmi Song, Sua Kim, Eslam R El-Sawy, Claudia Cerella, Barbora Orlikova-Boyer, Gilbert Kirsch, Christo Christov, Mario Dicato, Marc Diederich
• Journal: Marine drugs (Mar Drugs) Vol. 19 Issue 6 (May 21 2021) ISSN: 1660-3397 [Electronic] Switzerland
• PMID: 34063867 (Publication Type: Journal Article)

Chemical References

• A-1210477
• Antineoplastic Agents
• Cytotoxins
• Indoles
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Sulfonamides
• aplysinopsin
• Tryptophan

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology, toxicity)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Cell Cycle (drug effects)
• Cell Death (drug effects)
• Cell Line
• Cytotoxins (chemistry, pharmacology, toxicity)
• Drug Synergism
• Endoplasmic Reticulum Stress (drug effects)
• Humans
• Indoles (chemistry, pharmacology)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, pathology)
• Myeloid Cell Leukemia Sequence 1 Protein (antagonists & inhibitors)
• Sulfonamides (chemistry, pharmacology)
• Tryptophan (analogs & derivatives, chemistry, pharmacology, toxicity)
• Zebrafish