Cordycepin induces apoptosis in human pancreatic cancer cells via the mitochondrial-mediated intrinsic pathway and suppresses tumor growth in vivo

Abstract

BackgroundCordycepin, the main active ingredient of a traditional Chinese herbal remedy – extracted from Cordyceps sinensis – has been demonstrated as a very effective anti-inflammatory and antitumor drug. The present study investigated its antitumor effect on pancreatic cancer, a highly aggressive cancer with extremely poor prognosis due to malignancy, and clarified its underlying mechanism both in vitro and in vivo.MethodsThe antitumor viability of cordycepin on human pancreatic cancer MIAPaCa-2 and Capan-1 cells was determined by colony formation assays. Annexin V/PI double staining and flow cytometry assay were used to investigate whether cordycepin induced apoptosis and cell cycle arrest. The mitochondrial membrane potential (ΔΨm) was analyzed by Rhodamine 123 staining, and expression of related proteins evaluated by Western blot and immunohistochemistry, both on pancreatic cancer cells and tumor xenografts to reveal the potential mechanism for the effect of cordycepin. Furthermore, the in vivo efficacy was examined on nude mice bearing MIAPaCa-2 cell tumors treated by intraperitoneal injection of cordycepin (0, 15, and 50 mg/kg/d) for 28 days.ResultsCordycepin inhibited cell viability, proliferation and colony formation ability and induced cell cycle arrest and early apoptosis of human pancreatic cancer cells (MIAPaCa-2 and Capan-1) in a dose- and time-dependent manner. The same effect was also observed in vivo. Decrease of ΔΨm and upregulation of Bax, cleaved caspase-3, cleaved caspase-9, and cleaved PARP as well as downregulation of Bcl-2 both in vitro and in vivo indicated that the mitochondria-mediated intrinsic pathway was involved in cordycepin’s antitumor effect.ConclusionOur data showed that cordycepin inhibited the activity of pancreatic cancer both in vitro and in vivo by regulating apoptosis-related protein expression through the mitochondrial pathway and suggest that cordycepin may be a promising therapeutic option for pancreatic cancer.

BRD4 inhibitor nitroxoline enhances the sensitivity of multiple myeloma cells to bortezomib in vitro and in vivo by promoting mitochondrial pathway-mediated cell apoptosis

“…[33][34][35] Previous studies have confirmed that caspases and Bcl-2 family proteins, such as Bax and Bcl-2, serve important roles in the mitochondrial apoptotic pathway. [36][37][38] Mortenson et al 39 demonstrated that bortezomib triggered cell apoptosis in small cell lung cancer via decreasing Bcl-2 levels. The results of the present study revealed that nitroxoline markedly decreased the level of Bcl-2, and increased the levels of Bax, cleaved PARP and cleaved caspase-3 in a concentration-dependent manner in H929 and RPMI8226 cells.…”

The Inhibitory Effect of Cordycepin on the Proliferation of MCF-7 Breast Cancer Cells, and Its Mechanism: An Investigation Using Network Pharmacology-Based Analysis

“…Treatment with cordycepin also induces apoptosis through the mitochondria-mediated intrinsic apoptotic pathways indicated by translocation of Bax from the cytosol to the mitochondria, release of cytochrome c from the mitochondria to the cytosol, and activation of caspase-9. Caspase-9 is activated by apaf-1 (apoptosome) and activates caspase-3 and -7 [57,58]. In addition, treatment with cordycepin induces death receptor-mediated extrinsic apoptotic pathways, as indicated by the activation of caspase-8, which stimulates two parallel cascades.…”

<p>Se-Enriched <em>Cordyceps militaris</em> Inhibits Cell Proliferation, Induces Cell Apoptosis, And Causes G2/M Phase Arrest In Human Non-Small Cell Lung Cancer Cells</p>

“…Colony formation assay indicated that Se-enriched Cordyceps militaris plays an important role in the reduction of cell proliferation in NCI-H292 and A549 cells. Many anticancer drugs could target cell apoptosis to induce the death of cancer cells 25. Flow cytometric assay and Hoechst staining analysis demonstrated the promotive efficacy of Se-enriched Cordyceps militaris in NSCLC cell apoptosis.…”

“…The pro-apoptotic member BAX and the anti-apoptotic member BCL-2 belong to the BCL family 6. BCL-2 could prevent the release of cytochrome c, while the activation of BAX leads to the release of cytochrome C into the cytosol, resulting in activation of caspases 9 and 3, effector caspases, in the mitochondrial pathway of cell apoptosis 25,26. In this study, we found that the ratio of BCL-2/BAX at both mRNA and protein levels was reduced as the concentration of Se-enriched Cordyceps militaris increased in both NCI-H292 and A549 cells, indicating the pro-apoptotic role of Se-enriched Cordyceps militaris in NSCLC cells.…”