Synergistic inhibition of colon cancer cell growth with nanoemulsion-loaded paclitaxel and PI3K/mTOR dual inhibitor BEZ235 through apoptosis

Abstract

Colon cancer is the third most common cancer in the world, with drug resistance and metastasis being the major challenges to effective treatments. To overcome this, combination therapy with different chemotherapeutics is a common practice. In this study, we demonstrated that paclitaxel (PTX) together with BEZ235 exhibited a synergetic inhibition effect on colon cancer cell growth. Furthermore, nanoemulsion (NE)-loaded PTX and BEZ235 were more effective than the free drug, and a combination treatment of both NE drugs increased the efficiency of the treatments. BEZ235 pretreatment before adding PTX sensitized the cancer cells further, suggesting a synergistic inhibition effect through the phosphatidylinositol-3-kinases/protein kinase B/mammalian target of rapamycin pathway. The 50% inhibitory concentrations for BEZ235 were 127.1 nM and 145.0 nM and for PTX 9.7 nM and 9.5 nM for HCT-116 and HT-29 cells, respectively. When loaded with NE the 50% inhibitory concentrations for BEZ235 decreased to 52.6 nM and 55.6 nM and for PTX to 1.9 nM and 2.3 nM for HCT-116 and HT-29 cells, respectively. Combination treatment with 10 nM NE-BEZ235 and 0.6 nM and 1.78 nM NE-PTX could kill 50% of HCT-116 and HT-29, respectively. The cell death caused by the treatment was through apoptotic cell death, which coincided with decreased expression of anti-apoptotic protein B-cell lymphoma 2. Our data indicate that the combination therapy of PTX with the phosphatidylinositol-3-kinases/protein kinase B/mammalian target of rapamycin dual inhibitor BEZ235 using NE delivery may hold promise for a more effective approach for colon cancer treatment.

Optimization of Formulations Consisting of Layered Double Hydroxide Nanoparticles and Small Interfering RNA for Efficient Knockdown of the Target Gene

“…Therefore, this research has optimized and confirmed the LDH NP system for efficient in vitro delivery of genes to cancer cells, which is believed to be also applicable for the in vivo delivery for cancer gene therapy. 43 , 44 …”

Inhibition of PI3K/Akt/mTOR overcomes cisplatin resistance in the triple negative breast cancer cell line HCC38

“…Therefore, we chose the dual PI3K/mTOR inhibitor NVP-BEZ235 to address increased Akt activation in HCC38CisR. Synergy of NVP-BEZ235 has already been demonstrated for paclitaxel in colon cancer cells [ 30 ] and carboplatin in a triple negative breast cancer cell line [ 31 ]. Additionally, NVP-BEZ235 has already proven its ability to enhance cisplatin sensitivity in cisplatin resistant bladder cancer cell lines [ 32 ].…”

PD-L1 Distribution and Perspective for Cancer Immunotherapy—Blockade, Knockdown, or Inhibition

“…With PD-L1 regulatory mechanism being elucidated, the development of small molecule inhibitors sheds light on precise knockdown of aberrant oncogene expression. Compared to traditional chemotherapy, chemical inhibitors are more effective and less harmful to normal cells, with much clearer patient subset (4, 106). Like gene silencing method, the usage of chemical inhibitors can “turn off” the PD-L1 expression “pipeline.” Thus, the influence of chemical inhibitors on different PD-L1 formats is similar to that of gene silencing, with a potentially slower response depending on the target relevance to PD-L1 expression.…”