Daphnane Diterpenoids from Daphne genkwa Inhibit PI3K/Akt/mTOR Signaling and Induce Cell Cycle Arrest and Apoptosis in Human Colon Cancer Cells

Abstract

Seven new daphnane-type diterpenoids, daphgenkins A–G (1–7), and 15 known analogues (8–22) were isolated from the flower buds of Daphne genkwa. Their structures and absolute configurations were elucidated by spectroscopic data and calculated ECD analyses. The cytotoxicities of all daphnane-type diterpenoids (1–22) obtained were evaluated against three human colon cancer cell lines (SW620, RKO, and LoVo). Compounds 1, 12, and 13 exhibited cytotoxic effects against the SW620 and RKO cell lines, with IC50 values in the range of 3.0–9.7 μM. The most active new compound, 1, with an IC50 value of 3.0 μM against SW620 cells, was evaluated further for its underlying molecular mechanism. Compound 1 induced G0/G1 cell cycle arrest, leading to the induction of apoptosis in SW620 cells. Also, it induced cancer cell apoptosis by an increased ratio of Bax/Bcl-2, activated cleaved caspase-3 and caspase-9, and upregulated PARP. Finally, compound 1 significantly inhibited PI3K/Akt/mTOR signaling in SW620 cells. Together, the results suggest that compound 1 may be a suitable lead compound for further biological evaluation.

Pyrroline-5-Carboxylate Reductase-2 Promotes Colorectal Cancer Progression via Activating PI3K/AKT/mTOR Pathway

“…In particular, the phosphatidylinosito1-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway is one of the many mechanisms regulating cell cycle and apoptosis, wherein an abnormality in any of this pathway's components may cause tumour development [ 10 ]. More specifically, the PI3K/Akt/mTOR signal transduction pathway can induce tumorigenesis via multiple mechanisms: autophagy participation, cell apoptosis inhibition, and tumor suppressor protein p53 downregulation in the nucleus [ 11 , 12 ]. Given this information, PI3K/mTOR pathway inhibitors have successfully treated primary and metastatic CRC, making this pathway a promising target for clinical cancer treatment [ 13 ].…”

[11]-Chaetoglobosins from Pseudeurotium bakeri Induce G2/M Cell Cycle Arrest and Apoptosis in Human Cancer Cells

“…The Bcl-2 family, containing pro-apoptotic (Bax, Bad) and anti-apoptotic (Bcl-2) members, played an important role in promoting or inhibiting apoptosis triggered by mitochondrial dysfunction . The pro-apoptotic protein Bax induces the release of cytochrome c and the cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP), while the anti-apoptotic member Bcl-2 prevents the release of these mitochondrial proteins by interacting with and inhibiting Bax. , To explore the molecular mechanism of apoptosis, one of the most active compounds, 2 , was further investigated for the expression levels of several apoptosis-related markers in MCF-7 cells. As shown in Figure , compound 2 increased the levels of Bax, cytochrome c , cleaved caspase 3, and cleaved PARP and down-regulated the level of Bcl-2 dose dependently.…”

Yuanhuacin and Related Anti-Inflammatory and Anticancer Daphnane Diterpenes from Genkwa Flos—An Overview

“…Daphne genkwa is formidable source of daphnane-type diterpenes and flavonoids [ 107 ]. Here, we focused on yuanhuacin and related compounds, but there are other daphnanes in the flower buds of Daphne genkwa , such as the genkwanines [ 74 ], daphneresiniferins A and B [ 42 ], acutilonine F, wikstroemia factor M [ 21 ], daphgenkins A–G [ 108 ], genkwadanes A–D [ 5 ], neogenkwanine I [ 109 ], genkwalathins A–B [ 110 ] and others [ 20 ]. There are also a few iso-derivatives, such as iso-YC and iso-YD and a compound designated yuanhuaphnin with anti-inflammatory properties (but it is mentioned in a single publication) [ 78 ].…”