title: Effective inhibition of colon cancer cell growth with MgAl-layered double hydroxide (LDH) loaded 5-FU and PI3K/mTOR dual inhibitor BEZ-235 through apoptotic pathways.
abstract: Colon cancer is the third most common cancer and the third largest cause of cancer-related death. Fluorouracil (5-FU) is the front-line chemotherapeutic agent for colon cancer. However, its response rate is less than 60%, even in combination with other chemotherapeutic agents. The side effects of 5-FU also limit its application. Nanoparticles have been used to deliver 5-FU, to increase its effectiveness and reduce side effects. Another common approach for colon cancer treatment is targeted therapy against the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. A recently-invented inhibitor of this pathway, BEZ-235, has been tested in several clinical trials and has shown effectiveness and low side effects. Thus, it is a very promising drug for colon cancer treatment. The combination of these two drugs, especially nanoparticle-packed 5-FU and BEZ-235, has not been studied. In the present study, we demonstrated that nanoparticles of layered double hydroxide (LDH) loaded with 5-FU were more effective than a free drug at inhibiting colon cancer cell growth, and that a combination treatment with BEZ-235 further increased the sensitivity of colon cancer cells to the treatment of LDH-packed 5-FU (LDH-5-FU). BEZ-235 alone can decrease colon cancer HCT-116 cell viability to 46% of the control, and the addition of LDH-5-FU produced a greater effect, reducing cell survival to 8% of the control. Our data indicate that the combination therapy of nanodelivered 5-FU with a PI3K/Akt inhibitor, BEZ-235, may promise a more effective approach for colon cancer treatment.
authors: School of Biomedical Sciences, University of Queensland, St Lucia, Queensland, Australia ; Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales, Australia.
authors: Jiezhong
authors: J
authors: Chen
authors: GeneCology Research Centre, Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Maroochydore, Queensland, Australia.
authors: Renfu
authors: R
authors: Shao
authors: Australian Institute of Bioengineering and Nanotechnology, University of Queensland, St Lucia, Queensland, Australia.
authors: Li
authors: L
authors: Li
authors: Australian Institute of Bioengineering and Nanotechnology, University of Queensland, St Lucia, Queensland, Australia.
authors: Zhi Ping
authors: ZP
authors: Xu
authors: Australian Institute of Bioengineering and Nanotechnology, University of Queensland, St Lucia, Queensland, Australia.
authors: Wenyi
authors: W
authors: Gu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D006878:Hydroxides / Q000737:chemistry; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D053758:Nanoparticles / Q000737:chemistry*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D006878:Hydroxides; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib
keywords: 5-FU; BEZ-235; PI3K/Akt/mTOR; apoptosis; cell death; colon cancer HCT-116 cells; layered double hydroxide (LDH)