The radiotherapy-sensitization effect of cantharidin: Mechanisms involving cell cycle regulation, enhanced DNA damage, and inhibited DNA damage repair.

Abstract

BACKGROUND:

Cantharidin is an inhibitor of protein phosphatase 2 A (PP2A), and has been frequently used in clinical practice. In our previous study, we proved that cantharidin could arrest cell cycle in G2/M phase. Since cells at G2/M phase are sensitive to radiotherapy, in the present study, we investigated the radiotherapy-sesitization effect of cantharidin and the potential mechanisms involved.

METHODS:

Cell growth was determined by MTT assay. Cell cycle was evaluated by flow cytometry. DNA damage was visualized by phospho-Histone H2A.X staining. Expression of mRNA was tested by microarray assay and real-time PCR. Clinical information and RNA-Seq expression data were derived from The Cancer Genome Atlas (TCGA) pancreatic cancer cohort. Survival analysis was obtained by Kaplan-Meier estimates.

RESULTS:

Cantharidin strengthened the growth inhibition effect of irradiation. Cantharidin drove pancreatic cancer cells out of quiescent G0/G1 phase and arrested cell cycle in G2/M phase. As a result, cantharidin strengthened DNA damage which was induced by irradiation. Moreover, cantharidin repressed expressions of several genes participating in DNA damage repair, including UBE2T, RPA1, GTF2HH5, LIG1, POLD3, RMI2, XRCC1, PRKDC, FANC1, FAAP100, RAD50, RAD51D, RAD51B and DMC1, through JNK, ERK, PKC, p38 and/or NF-κB pathway dependent manners. Among these genes, worse overall survival for pancreatic cancer patients were associated with high mRNA expressions of POLD3, RMI2, PRKDC, FANC1, RAD50 and RAD51B, all of which could be down-regulated by cantharidin.

CONCLUSION:

Cantharidin can sensitize pancreatic cancer cells to radiotherapy. Multiple mechanisms, including cell cycle regulation, enhanced DNA damage, and inhibited DNA damage repair, may be involved.

• Authors: Meng-Dan Xu, Shu-Ling Liu, Bei-Bei Zheng, Jing Wu, Meng-Yao Wu, Yan Zhang, Fei-Ran Gong, Min Tao, Junning Zhang, Wei Li
• Journal: Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] (Pancreatology) Vol. 18 Issue 7 Pg. 822-832 (Oct 2018) ISSN: 1424-3911 [Electronic] Switzerland
• PMID: 30201439 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Chemical References

• Radiation-Sensitizing Agents
• Protein Phosphatase 2
• Cantharidin

Topics

• Cantharidin (pharmacology)
• Cell Cycle
• Cell Division (drug effects, radiation effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects, radiation effects)
• DNA Damage
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Pancreatic Neoplasms
• Protein Phosphatase 2 (antagonists & inhibitors)
• Radiation-Sensitizing Agents (pharmacology)
• Radiotherapy