The anti-tumor effect of pachymic acid on osteosarcoma cells by inducing PTEN and Caspase 3/7-dependent apoptosis

Abstract

Pachymic acid (PA) is a lanostane type triterpenoid isolated from Poria cocos, which possesses an anti-tumor effect in breast cancer, prostate cancer, lung cancer, and bladder cancer cells. In this study, we investigated the effect of PA on the growth and apoptosis of human immortalized cell line (HOS) and primary osteosarcoma cells by a Cell Counting Kit-8 (CCK-8) and Annexin V and propidium iodide (PI) staining, respectively. Western blot was used to measure the expression of cleaved Caspase 3, PTEN, and AKT, as well as the AKT phosphorylation. The Caspase 3 activity was determined using the Caspase-3 Colorimetric Assay Kit. From the results, PA significantly reduced cell proliferation in a concentration- and time-dependent manner. PA also induced cell apoptosis in a dose-dependent fashion. PA treatment led to increased Caspase 3 activation and PTEN expression, as well as reduced AKT phosphorylation. Moreover, Ac-DEVD-CHO (a Caspase 3/7 inhibitor) pre-treatment or PTEN knockdown partially blocked the effects of PA on cell proliferation and apoptosis. Caspase 3/7 inhibitor had an additive effect with PTEN knockdown. Collectively, our results suggested that induction of apoptosis by PA was mediated in part by PTEN/AKT signaling and Caspase 3/7 activity. This study provides evidence that PA might be useful in the treatment of human osteosarcoma.

Targeting Pyruvate Kinase M2 and Hexokinase II, Pachymic Acid Impairs Glucose Metabolism and Induces Mitochondrial Apoptosis

“…PA stimulated the production of ROS and depletion of ATP (Fig. 5b); this result was consistent with the work of Jeong et al 9) Furthermore, through the inhibition of HK2 and activation of PKM2, PA decreased the intermediate PPP level for NADPH generation and ROS scavenging, which may have contributed to the stimulation of ROS. 26) ROS can activate intrinsic and extrinsic apoptosis pathways and modulate the pro-apoptotic molecules, including MAPK, Bax, and Bcl2; moreover, it can regulate the expression levels of various transcription factors, including Sp1, AP1, and NF-κB, and other pro-oncogenic genes that are engaged in cancer cell proliferation, survival, and metastasis.…”

“…39) In the study of Jeong et al, blocking of ROS by N-acetyl-L-cysteine, which is a ROS scavenger, effectively reduced the PA-induced apoptosis. 9) Moreover, ROS-mediated ER stress is associated with apoptosis initiation, which has been observed in PAtreated lung cancer cells. 4,40) In summary, ROS generation by PA may be a fundamental mechanism for the anti-cancer activity of PA.…”

“…3) Moreover, PA suppresses the growth and invasiveness of EJ bladder cancer, osteosarcoma, and gastric cancer cells. [9][10][11] PA has gained research attention, but the mechanisms of its anti-inflammation and anti-cancer effects remain unclear.…”

The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer

“…In addition, knockdown of GSDME reduced the proapoptotic effect of Dioscin on OS 47 .In another study, Rogers et al 14 also found that the role of GSDME in targeting the mitochondria to promote caspase-3 dependent apoptosis, and the GSDME-N terminal domain can be located on cardiolipin on the mitochondrial membrane, forming a membrane pore effect, leading to the release of cytochrome-c, and then amplifying the internal signaling pathway of apoptosis. Wen et al 48 found that a lanostane type triterpenoid isolated from Poria cocos, Pachymic acid (PA),can suppress cell proliferation by the induction of caspase 3-mediated apoptosis in an immortalized cell line (HOS) and primary osteosarcoma. Li et al 49 claimed that Bcl-2 might be a direct target of miR-143.…”

Phytochemistry and Pharmacological Activities of Wolfiporia cocos (F.A. Wolf) Ryvarden & Gilb

“…The results showed that compound 1 had markedly inhibition efficiency on human primary osteosarcoma cells proliferation concentration-and time-dependently. Meanwhile, compound 1 induced cell apoptosis dose-dependently, activated caspase 3, up-regulated PTEN expression and reduced AKT phosphorylation, demonstrating that compound 1 might be effective in treating human osteosarcoma (Wen et al, 2018). The anti-tumor activity of compound 1 was observed on nasopharyngeal carcinoma (NPC) cells and it was found that compound 1 might obviously inhibit cell proliferation and dose-dependently promote the apoptosis of the human NPC cells.…”