Platycodin D induces apoptotic cell death through PI3K/AKT and MAPK/ERK pathways and synergizes with venetoclax in acute myeloid leukemia

  • Eur J Pharmacol. 2023 Aug 3;956:175957. doi: 10.1016/j.ejphar.2023.175957.
Xia Jiang  1 ,  Ye Lin  2 ,  Mengting Zhao  2 ,  Youhong Li  1 ,  Peipei Ye  3 ,  Renzhi Pei  3 ,  Ying Lu  4 ,  Lei Jiang  5
Affiliations
  • 1. Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, China; Department of Pathology and Pathogenic Biology, and Zhejiang Key Laboratory of Pathophysiology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, China; Institute of Hematology, Ningbo University, Ningbo, China.
  • 2. Department of Pathology and Pathogenic Biology, and Zhejiang Key Laboratory of Pathophysiology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, China.
  • 3. Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, China; Institute of Hematology, Ningbo University, Ningbo, China.
  • 4. Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, China; Institute of Hematology, Ningbo University, Ningbo, China. Electronic address: [email protected].
  • 5. Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, China; Department of Pathology and Pathogenic Biology, and Zhejiang Key Laboratory of Pathophysiology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, China. Electronic address: [email protected].
PMID: 37541375 DOI: 10.1016/j.ejphar.2023.175957
Abstract

Acute myeloid leukemia (AML) is a highly heterogeneous and rapidly progressive hematopoietic neoplasm characterized by frequent relapses and variable prognoses. The development of new treatment options, therefore, is of crucial importance. Platycodin D (PD) is a triterpenoid saponin, extracted from the roots of the traditional Chinese herbal medicine Platycodon grandiflorum (Jacq.) A. DC., which has been reported to exhibit therapeutic potential against a broad range of cancers. Although the effects of PD on AML remain unclear, in the present study, we observed a concentration-dependent reduction in the viability of multiple human AML cell lines in response to treatment with PD. In addition to triggering mitochondria-dependent Apoptosis via the upregulation of Bak and Bim, treatment with PD also induced cell cycle arrest at the G0/G1 phase. Western blot analyses revealed marked suppression of the phosphorylation of protein kinase B (Akt), glycogen synthase kinase-3β, ribosomal protein S6, and extracellular signal-regulated kinase (ERK) by PD, in turn implying the participation of the phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/ERK pathways. Pre-incubation with LY294002, MK2206, AR-A014418, or U0126 was consistently found to significantly aggravate PD-induced inhibition of viability. Additionally, PD combined with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax elicited synergistically enhanced cytotoxic effects. The anti-leukemic activity of PD was further validated using primary samples from de novo AML patients. Given the results of the present study, PD may be a potent therapeutic candidate for the treatment of AML.

Keywords
Acute myeloid leukemia; Apoptosis; Platycodin D; Venetoclax.
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