Synergistic antitumor activity of reversine combined with aspirin in cervical carcinoma in vitro and in vivo

Abstract

A recent report showed that reversine treatment could induce murine myoblasts dedifferentiation into multipotent progenitor cells and inhibit proliferation of some tumors, and other reports showed that apoptosis of lung adenocarcinoma cells could be induced by aspirin. The aim of the present study was to evaluate the synergistic antitumor effects of reversine and aspirin on cervical cancer. The inhibition rate of reversine and aspirin on cervical cancer cell lines' (HeLa and U14) was determined by MTT method, cell cycle of HeLa and U14 cells was analyzed by FACS, mitochondrial membrane potential of HeLa and U14 was detected using a JC-1 kit. HeLa and U14 colony formation was analyzed by soft agar colony formation assay. The expression of caspase-3, Bcl-2/Bax, cyclin D1 and p21 was detected by qRT-PCR and Western Blotting. Moreover, tumor weight and tumor volume was assessed using a murine model of cervical cancer with U14 cells subcutaneously (s.c.) administered into the neck, separately or combined with drug administration via the intraperitoneal (i.p.) route. The inhibition rate of cells in the combination group (10 lmol/L reversine, 10 mmol/ L aspirin) increased significantly in comparison to that when the drugs were used alone (P \ 0.05); moreover, this combination could synergistically inhibit the proliferation of five cervical cancer cell lines (HeLa, U14, Siha, Caski and C33A). In the therapeutic mouse model, tumor weight and tumor volume of cervical cancer bearing mice was more reduced when compared with the control agents (P \ 0.05) in tumor-bearing mice. The combination of reversine and aspirin exerts synergistic growth inhibition and apoptosis induction on cervical cancers cells.

Reversine Induced Multinucleated Cells, Cell Apoptosis and Autophagy in Human Non-Small Cell Lung Cancer Cells

“…The anti-tumor behavior of reversine has also been demonstrated in multiple cancers including of melanoma, oral cancer, breast cancer, thyroid cancer, colon cancer, cervical cancer, etc. [ 5 , 7 – 9 , 11 , 14 , 15 ], and our findings in this study are similar with these reports. The IC50 of reversine in the reported cancer cells are 1 to 20 μM.…”

“…The induction of apoptosis by reversine has been reported in several human tumors [ 7 , 9 , 11 , 14 , 15 ]. However, this is the first time to observe the induction of apoptosis by reversine in human NSCLS cells.…”

Mutations in PIK3CA sensitize breast cancer cells to physiologic levels of aspirin

“…The study by Lloyd et al reported that aspirin suppresses cell adhesion and cell motility in the prostate cancer cell line PC-3 [ 50 ]. Lastly, aspirin treatment decreased the invasiveness of the human cervical cancer cell line Hela [ 51 ]. Although these properties are hallmarks of cancer, none of these studies show an association with mutant PIK3CA status, as all of these cell lines only carry wild-type PIK3CA, with the exception of MCF-7.…”

Resolving cancer–stroma interfacial signalling and interventions with micropatterned tumour–stromal assays

“…Reversine is a synthetic purine that was originally discovered capable of dedifferentiating murine myoblasts to regain multipotency 55 . It has recently been found to possess antitumor capabilities, the exact mechanisms of which have not been clearly defined 8 , 56 , 57 , 58 , 59 , 60 , 61 , 62 . The structural analogy of reversine to ATP implies its major function as a kinase inhibitor 8 .…”

“…In vivo , reversine was shown to mildly inhibit multiple myeloma growth in a mouse model with intravenous injection of tumor cells, but not with subcutaneous inoculation, indicating a role of the native bone marrow stromal environment in reversine-induced anti-myeloma activities 8 . Two more recent studies demonstrated that reversine inhibited subcutaneous human cervical and thyroid cancer cell growth in nude mouse models 61 , 62 . Interestingly, both reports showed a mild, delayed tumor growth inhibition by reversine compared to DMSO treatments, with onsets of inhibition between 19 and 40 days after implantation, similar to the growth dynamics in the current study.…”