cheliensisin-a and Colonic-Neoplasms

Chiliensisine A (Chel A) as a novel styryl-lactone isolated from Goniothalamus cheliensis Hu has been indicated to be a chemotherapeutic agent in Leukemia HL-60 cells. However, its potential for cancer treatment and the underlying mechanisms are not deeply investigated to the best of our knowledge. Current studies showed that Chel A could trigger p53-mediated apoptosis, accompanied with dramatically inhibition of anchorage-independent growth of human colon cancer HCT116 cells. Further studies found that Chel A treatment resulted in p53 protein stabilization and accumulation via the induction of its phosphorylation at Ser20 and Ser15. Moreover, Chel A-induced p53 protein accumulation and activation required ATR/Chk2 axis, which is distinct from the mechanism that we have most recently identified the Chk1/p53-dependent apoptotic response by Chel A in normal mouse epidermal Cl41 cells. In addition, our results demonstrated that hydrogen peroxide generation induced by Chel A acted as a precursor for all these signaling events and downstream biological effects. Taken together, we have identified the Chel A as a new therapeutic agent, which highlights its potential for cancer therapeutic effect.

Topics: Apoptosis; Ataxia Telangiectasia Mutated Proteins; Checkpoint Kinase 2; Colonic Neoplasms; Epoxy Compounds; HCT116 Cells; Humans; Hydrogen Peroxide; Pyrones; Signal Transduction; Transfection; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

Growing attentions have been focused on natural antitumor drugs. Recently, a novel and potent antitumor drug Cheliensisin A (GC-51) with broad-spectrum efficiency has been developed. However, due to its poor water solubility and chemical instability, choosing the appropriate dosage form is of great significance. This study aimed at developing a lyophilized submicron emulsion for GC-51 and further improving the therapeutic index of the drug. The resultant lyophilized GC-51 submicron emulsion was much more stable than its solution, which can be stored for years without significant change on physicochemical properties. And its solubility was increased from 6.74+/-0.14 to 2.00+/-0.10 mg mL(-1). The 50% inhibitory concentration IC50 values were calculated from growth curves by MTT assay on various tumor cell lines. Compared with the IC50 of GC-51 crude drug, that of lyophilized GC-51 submicron emulsion decreased from 24.04+/-1.97 to 8.23+/-1.84 microg mL(-1) on HepG2, and from 31.08+/-2.56 to 10.85+/-2.09 microg mL(-1) on CT-26, from 17.90+/-1.83 to 7.49+/-1.87 microg mL(-1) on HeLa and from 16.38+/-2.41 to 10.13+/-2.12 microg mL(-1) on A549, respectively. In the time-dependent assay of tumor cell viability, lyophilized GC-51 submicron emulsion exhibited significantly lower inhibition rate in the initial action times, but increased gradually afterwards. That means lyophilized submicron emulsion as the vector for GC-51 had some protective and delayed release effect. Further, the in vivo therapeutic efficacy was measured in pulmonary metastasis of colon cancer-bearing BALB/c mice model. An obvious enhanced antitumor activity was observed after administration of lyophilized GC-51 submicron emulsion (P<0.05), which increased from 22.78+/-3.5 to 41.42+/-4.2% compared with GC-51 injection. And the life span of tumor-bearing mice in lyophilized GC-51 submicron emulsion group was significantly longer than that of the mice in GC-51 injection and normal saline groups. Compared with crude drug, the lyophilized GC-51 submicron emulsion showed a significantly higher antitumor efficiency both in vivo and in vitro, suggesting a potential application in tumor chemotherapy.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Chemical Phenomena; Chemistry, Physical; Colonic Neoplasms; Drug Stability; Electrochemistry; Emulsions; Epoxy Compounds; Female; Freeze Drying; HeLa Cells; Humans; Injections, Intravenous; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Microscopy, Electron, Transmission; Nanoparticles; Particle Size; Pyrones; Solubility; Survival Analysis