AS1041, a Novel Synthesized Derivative of Marine Natural Compound Aspergiolide A, Arrests Cell Cycle, Induces Apoptosis, and Inhibits ERK Activation in K562 Cells.

Fengli Yuan,Yinghan Chen,Dehai Li,Jing Li,Liang Qiao,Ming Liu,Qianqun Gu,Yankai Liu,Xin Qi

doi:10.3390/md15110346

Abstract

AS1041 is a novel synthesized anthraquinone lactone derivative of marine natural compound aspergiolide A (ASP-A) with new structure skeleton and marked cytotoxicity in cancer cells. To study its cytotoxicity in detail, we evaluated its activity on human K562 chronic myelogenous leukemia cells and investigated the related molecule mechanisms. AS1041 significantly inhibited the proliferation and colony formation of K562 cells. Moreover, AS1041 arrested cell cycle progression at G2/M phase in a concentration-dependent manner, and also caused concentration- and time-dependent induction of apoptosis. In addition, the molecular mechanisms investigation showed that AS1041 did not localize in the cellular nucleus and did not affect topoisomerases I or II. However, AS1041 could inactivate extracellular signal-regulated kinase (ERK) and contribute to AS1041-induced apoptosis. We concluded that AS1041 was cytotoxic to K562 leukemia cells and the cytotoxicity related to the cell cycle arrest, apoptosis induction, and ERK inhibition. These results implied that AS1041 was a novel derivative of ASP-A with significant cytotoxicity to chronic myelogenous leukemia cells and may have therapeutic potential for the treatment of cancer and leukemia.

Highlights

We found that cleaved caspase-3 (C-Cas3), cleaved caspaseand C-Poly-adenosine diphosphate-ribose polymerase (PARP) significantly increased after AS1041 treatment
We found that activation of P-extracellular signal-regulated kinase (ERK) was significantly inhibited after AS1041 treatment, without any effect on the total protein of ERK, and the inhibition was both in a concentration- and time-dependent manner (Figure 7c,d)
When combined with imatinib and AS1041, all the combination index (CI) values were smaller than 1, indicating the potent synergism between AS1041 and imatinib on the inhibition of K562 cells proliferation and the chemosensitizing effect of AS1041. This result further confirmed AS1041 inactivated ERK in K562 cells. All these results indicated that AS1041 induced K562 cells apoptosis by inhibition of phosphatidylinositol kinase/protein kinase B/mammalian target of (P-ERK) activation

Summary

Introduction

Natural products, or their derivatives, represent more than half of the clinical cancer chemotherapeutic agents, such as etoposide, taxanes, and camptothecines [1,2,3]. Due to the special chemical and physical conditions of marine ecology, marine organisms biosynthesize a variety of molecules with unique chemical structures. These compounds provide multiple and potent pharmacological activities [4]. The great progress in the anticancer area using marine drugs make us believe that it is a valid method to search anticancer drugs from marine natural compounds or their synthesized derivatives

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Conclusion