Paclitaxel/Tetrandrine Coloaded Nanoparticles Effectively Promote the Apoptosis of Gastric Cancer Cells Based on “Oxidation Therapy”

Abstract

Paclitaxel (Ptx) has demonstrated encouraging activity in the treatment of gastric cancer. Development of drug-containing biodegradable polymeric nanoparticles (np) becomes one of the solutions to relieve side effects of Ptx. However, Ptx-loaded nanoparticles prepared by the nanoprecipitation method are unstable in the aqueous phase. Here we report that tetrandrine (Tet) effectively increases the stability of Ptx-loaded nanoparticles when Tet is coencapsulated with Ptx into mPEG-PCL nanoparticles. The current study demonstrates the synergistic antitumor effect of Tet and Ptx against gastric cancer cells, which provides the basis of coadministration of Tet and Ptx by nanoparticles. It is reported that the cellular chemoresistance to Ptx correlates with intracellular antioxidant capacity and the depletion of cellular antioxidant capacity could enhance the cytotoxicity of Ptx. Tet effectively induces intracellular ROS production. Therefore, the present study provides a promising novel therapeutic strategy basing on "oxidation therapy" that it could amplify the antitumor effect of paclitaxel by employing Tet as a pro-oxidant. More intracellular Tet accumulation by endocytosis of Ptx/Tet-np than equivalent doses of free drug leads to more intracellular ROS induction, which could efficiently enhance the cytotoxicity of Ptx by sequential inhibition of ROS-dependent Akt pathway and activation of apoptotic pathways, all of which would mediate the superior cytotoxicity of Ptx/Tet-np over free drug. The present results suggest that the codelivery of Ptx and Tet by nanoparticles provides a novel therapeutic strategy basing on "oxidation therapy" against gastric cancer.

Tetrandrine induces cell death in SAS human oral cancer cells through caspase activation-dependent apoptosis and LC3-I and LC3-II activation-dependent autophagy

“…Thus, it is necessary to identify and develop new anticancer agents that will selectively target the tumor. It was reported that the induction of apoptosis through the caspase cascade triggered by tetrandrine has inhibitory effects to various tumor cells (20,21,27,37). Many studies have demonstrated that tetrandrine has pharmacologic potential in cancer therapy but to date the effects of tetrandrine on human oral cancer is little known and have not been identified and reported in oral cancer cells.…”

“…Tetrandrine (C 38 H 42 O 8 N 2 ), a bisbenzylisoquinoline alkaloid, was isolated from the root of Stephania tetrandra S. Moore, has been used as an anti-inflammatory, antipyretic and analgesic herb in Chinese medicine (15)(16)(17)(18), furthermore, in myocyte and Tetrandrine induces cell death in SAS human oral cancer cells through caspase activation-dependent apoptosis and LC3-I and LC3-II activation-dependent autophagy vascular smooth muscle cells, tetrandrine inhibits the I Ca-L and reduces Ca 2+ flows into the cytosol (19,20). Tetrandrine has been found to induce cytotoxic effect such as the inhibiting proliferation and inducing apoptosis of various cancer cells such as breast cancer, lung cancer, neuroblastoma, Burkitt's lymphoma, hepatoma, glioma, leukemia and colon cancer (21)(22)(23)(24)(25). Tetrandrine induced G0/G1 phase arrest in Neuro 2a mouse neuroblastoma cells (26) and human Hep G2 cells (27).…”

An efficient Trojan delivery of tetrandrine by poly(N-vinylpyrrolidone)-block-poly(ε-caprolactone) (PVP-b-PCL) nanoparticles shows enhanced apoptotic induction of lung cancer cells and inhibition of its migration and invasion

“…23 In our previous studies, Tet-loaded mPEG-PCL nanoparticles showed an antitumor effect in several gastrointestinal cancer cell lines. [24][25][26] We demonstrated that Tet-loaded mPEG-PCL nanoparticles showed enhanced antitumor efficiency compared to free Tet through more efficient penetration of cell membrane by endocytosis. 25 Recently the application of nanoparticle systems in tumor imaging and therapy has attracted more and more interest.…”

“…As demonstrated in our previous studies, cellular uptake of nanoparticles is mediated by endocytosis, which penetrates cell membranes more efficiently than the infiltration of small molecules. [24][25][26]48,49 Therefore, cellular uptake of TetNPs mediated by endocytosis leads to more intracellular Tet accumulation, thereby more effectively regulating the …”

Nanomedicine-Mediated Combination Drug Therapy in Tumor

“…Hyaluronic acid-decorated PLGA nanoparticles Breast cancer, squamous cell carcinoma [19] Paclitaxel and etoposide PEG-PLGA nanoparticles Osteosarcoma [20] Cisplatin and paclitaxel Folic acid modified PEG-PLGA nanoparticles Non-small lung cancer [21,22] Cisplatin and doxorubicin Transferrin modified PEG-PLGA nanoparticles Human hepatoma carcinoma [23] Combretastatin-A4 phosphate and doxorubicin mPEG-PLA nanoparticles Human nasopharyngeal epidermal carcinoma [24] Paclitaxel and tetrandrine CTAB@MSN Breast cancer [25] mPEG-PCL nanoparticles Gastric cancer [27] PEG-b-PCL nanoparticles Gastric cancer [28] Pirarubicin and paclitaxel Human serum albumin nanoparticles Breast cancer [15] Hypocrellin B and paclitaxel Hyaluronic acid-ceramide nanoparticles Lung cancer [29] Doxorubicin and paclitaxel mPEsG-b-PLG-b-PLL/DOCA nanovehicle Non-small cell lung cancer [30] PEG-PLGA and PEG-PLA nanoparticles have also been chemically altered to improve tumor targeting. For example, He et al [21,22] utilized folic acid (FA)-modified PEG-PLGA nanoparticles for the co-delivery of cisplatin (CDDP) and PTX.…”