Mitochondria-Modulating Liposomes Reverse Radio-Resistance for Colorectal Cancer.
Junmei LiYuhong WangWenhao ShenZiyu ZhangZhiyue SuXia GuoPei PeiLin HuTeng LiuKai YangLingchuan GuoPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2024)
Complete remission of colorectal cancer (CRC) is still unachievable in the majority of patients by common fractionated radiotherapy, leaving risks of tumor metastasis and recurrence. Herein, clinical CRC samples demonstrated a difference in the phosphorylation of translation initiation factor eIF2α (p-eIF2α) and the activating transcription factor 4 (ATF4), whose increased expression by initial X-ray irradiation led to the resistance to subsequent radiotherapy. The underlying mechanism is studied in radio-resistant CT26 cells, revealing that the incomplete mitochondrial outer membrane permeabilization (iMOMP) triggered by X-ray irradiation is key for the elevated expression of p-eIF2α and ATF4, and therefore radio-resistance. This finding guided to discover that metformin and 2-DG are synergistic in reversing radio resistance by inhibiting p-eIF2α and ATF4. Liposomes loaded with metformin and 2-DG (M/D-Lipo) are thus prepared for enhancing fractionated radiotherapy of CRC, which achieved satisfactory therapeutic efficacy in both local and metastatic CRC tumors by reversing radio-resistance and preventing T lymphocyte exhaustion.
Keyphrases
- transcription factor
- early stage
- drug delivery
- radiation induced
- poor prognosis
- signaling pathway
- endoplasmic reticulum stress
- radiation therapy
- induced apoptosis
- locally advanced
- dual energy
- squamous cell carcinoma
- ejection fraction
- cell death
- newly diagnosed
- cancer therapy
- chronic kidney disease
- cell cycle arrest
- risk assessment
- peripheral blood
- reactive oxygen species
- protein kinase