16-Hydroxycleroda-3, 13-dien-15, 16-olide inhibits the proliferation and induces mitochondrial-dependent apoptosis through Akt, mTOR, and MEK-ERK pathways in human renal carcinoma cells

Cheng Liu, Wei Chang Lee, Bu Miin Huang, Yi Chen Chia, Yu Chi Chen, Yung Chia Chen

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background Renal cell carcinoma (RCC) is well known that it cannot be treated with traditional chemotherapy or radiotherapy. 16-Hydroxycleroda-3,13-dien-15,16-olide (CD), isolated from Polyalthia longifolia Benth. & Hook. f. var. pendula had been reported to display significant efficacy against cancer cell lines. Purpose To determine the anti-tumour activities of CD in two clear cell type RCC (ccRCC) cell lines (A-498 and 786-O). In addition, the underlying mechanisms were also examined. Methods The cell viabilities of CD-treated ccRCC cells were examined by MTT assay. The apoptotic features were confirmed by acridine orange and ethidium bromide staining. 2′,7′-dichlorofluorescin diacetate was used to check reactive oxygen species (ROS) involvement. Mitochondria membrane potential (MMP) were determined by using fluorescent dyes, rhodamine 123 and 5′,6,6′-tetrachloro-1,1′,3,3′-tetraethyl benzimidazolylcarbocyanine iodide (JC-1). Proapoptotic, anti-apoptotic proteins and intracellular signaling molecules involved in CD-induced apoptosis were examined by Western blot analysis. Results CD inhibited both 786-O and A-498 cell proliferation and induced a series apoptotic characteristics expressions, ROS accumulation, caspase-3 activation as well as poly-(ADP-ribose) polymerase cleavage in both ccRCC cells. Additionally, CD caused MMP reduction and cytochrome c release from mitochondria as well as inhibition of anti-apoptotic proteins, including B cell lymphoma 2 and heat shock protein 70. Mechanically, we address that CD suppressed cell proliferation and induced apoptosis via induction of FOXO3a as well as decreased phosphorylation of Akt, mTOR, MEK/ERK and their downstream molecules, cMyc and hypoxia inducible factor 2α expression in a concentration- and time-dependent trend. Conclusion CD caused cell death through ROS overproduction and induction of mitochondria-dependent apoptotic pathway in ccRCC cells that accompanied with multiple oncogenic signals inactivation.

Original languageEnglish
Pages (from-to)95-107
Number of pages13
JournalPhytomedicine
Volume36
DOIs
Publication statusPublished - 2017 Dec 1

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine

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