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Theranostics 2021; 11(9):4281-4297. doi:10.7150/thno.51193 This issue Cite

Research Paper

Combination of long-acting TRAIL and tumor cell-targeted photodynamic therapy as a novel strategy to overcome chemotherapeutic multidrug resistance and TRAIL resistance of colorectal cancer

Tianshan She^1*, Qiuxiao Shi^1*, Zhao Li^1*, Yanru Feng¹, Hao Yang^1,2, Ze Tao¹, Heng Li¹, Jie Chen¹, Shisheng Wang³, Yan Liang⁴, Jingqiu Cheng^1,2✉, Xiaofeng Lu^1,2✉

1. Key Lab of Transplant Engineering and Immunology, MOH, Regenerative Medical Research Center, West China Hospital, Sichuan University, Chengdu 610041, China.
2. Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
3. West China-Washington Mitochondria and Metabolism Research Center, West China Hospital, Sichuan University, Chengdu 610041, China.
4. Histopathology Platforms of Experimental Center, West China Hospital, Sichuan University, Chengdu 610041, China.
* These authors contributed equally to this work.

✉ Corresponding authors: xiaofengluedu.cn (XF Lu) or jqchengedu.cn (JQ Chen)

Abstract

Chemotherapeutic multidrug resistance (MDR) is the major hindrance for clinical therapy of colorectal cancer (CRC). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with selective cytotoxicity might overcome MDR of CRC cells. Unfortunately, cross-resistance to TRAIL has been detected in many CRC cells, suggesting the need to combine TRAIL with sensitizers to combat refractory CRC. Our purpose is to explore the potential of combination therapy of TRAIL and tumor-cell targeted photodynamic therapy (PDT) in combating CRC with both chemotherapeutic MDR and TRAIL resistance.

Methods: Tumor cell-targeted PDT was performed using a Ze-IR700 photosensitizer with high affinity for epidermal growth factor receptor (EGFR). The impact of PDT on the gene expression of CRC cells was revealed by RNA sequencing. The synergistic antitumor effect of long-acting TRAIL and PDT was evaluated in mice bearing tumor grafts of CRC cells with both chemotherapeutic MDR and TRAIL resistance.

Results: Chemotherapeutic MDR and TRAIL resistance are common in CRC cells. Pretreatment of CRC cells with tumor cell-targeted PDT significantly (10-60 times) increased the sensitivity of these CRC cells to TRAIL by upregulating death receptors. Combination therapy, but not monotherapy, of long-acting TRAIL and PDT greatly induced apoptosis of CRC cells, thus efficiently eradicated large (~150 mm³) CRC tumor xenografts in mice.

Conclusions: Tumor cell-targeted PDT extensively sensitizes CRC cells to TRAIL. Combination therapy of long-acting TRAIL and PDT is promising to combat CRC with both chemotherapeutic MDR and TRAIL resistance, which might be developed as a novel strategy for precision therapy of refractory CRC.

Keywords: Tumor necrosis factor-related apoptosis-inducing ligand, Photodynamic therapy, Multidrug resistance, Cancer targeted therapy, Colorectal cancer.

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