Combination therapy using Cel-CSO/Taxol NPs for reversing drug resistance in breast cancer through inhibiting PI3K/AKT/NF-κB/HIF-1α pathway.
Huahui ZengXiaohu ZengCan WangGuoqiang WangQikang TianJunwei ZhaoLingzhou ZhaoRuiqin LiYing LuoHaotian PengZhenqiang ZhangXiaofang LiXiangxiang WuPublished in: Drug delivery and translational research (2024)
The resistance of malignant tumors to multiple drugs is a significant obstacle in cancer treatment and prognosis. Accordingly, we synthesized a celastrol (Cel) prodrug (Cel-CSO) by conjugating chitosan oligosaccharides (CSO) to Cel for reversing Taxol resistance in chemotherapy, followed by self-assembly with Taxol into a novel nanoplatform of Cel-CSO/Taxol nanoparticles (termed NPs). NPs showed a suitable size (about 153 nm), excellent stability and prolonged release of Cel and Taxol in a manner that depended on both pH and time. NPs effectively inhibited the overexpression of multidrug resistance-related protein P-gp, hypoxia inducible factor-1α (HIF-1α), and triggered the MCF-7/Taxol cell apoptosis through inhibiting the PI3K/AKT/NF-κB/HIF-1α pathway. In tumor-bearing mice, NPs exhibited significant curative effects in inducing apoptosis of MCF-7/Taxol tumors which showed a low expression level of P-gp, microtubule-related proteins TUBB3 and Tau. The results indicated that NPs may be a promising strategy to overcome drug resistance caused by P-gp, which improve the antitumor effects in drug-resistant breast cancer.
Keyphrases
- signaling pathway
- pi k akt
- drug resistant
- oxide nanoparticles
- cell cycle arrest
- cell proliferation
- combination therapy
- oxidative stress
- endothelial cells
- multidrug resistant
- breast cancer cells
- photodynamic therapy
- poor prognosis
- drug delivery
- cell death
- cancer therapy
- metabolic syndrome
- drug release
- nuclear factor
- cystic fibrosis
- toll like receptor
- radiation therapy
- squamous cell carcinoma
- rectal cancer
- prognostic factors
- young adults