2. Academic Validation
  3. A novel photosensitizer berberine derivative B12 induces apoptosis and suppresses HIF-1α expression in colorectal cancer cells via mitochondria-to-nucleus sequential-targeting

A novel photosensitizer berberine derivative B12 induces apoptosis and suppresses HIF-1α expression in colorectal cancer cells via mitochondria-to-nucleus sequential-targeting

  • Acta Pharmacol Sin. 2026 Jan 20. doi: 10.1038/s41401-025-01728-y.
Wen-Bin Pei # 1,  Zi-Yu Lei # 1 2 3,  Fu-Quan Xie # 4 5,  Peng Chen 6,  Yong-Cheng Su 1 2,  Yu-Shan Qin 6,  Jiang-Quan Li 1,  Qian-Wen Shen 1,  Miao-Miao Ma 1,  Chun-Yi Gao 1,  Jia-Chen Zhu 1,  Ya-Jie Xu 1,  Kai-Yue Zhang 1,  Wen-Qing Zhang 1,  Yan-Dong Zhang 7,  Tian-Hui Hu 8 9 10 11,  Bei-Bei Xu 12 13
Affiliations

Affiliations

  • 1 Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China.
  • 2 Cancer Hospital, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China.
  • 3 Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou, 341000, China.
  • 4 Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, 400037, China.
  • 5 Chongqing Key Laboratory of Precision Medicine and Prevention of Major Respiratory Diseases, Chongqing, 400037, China.
  • 6 Department of Chemistry and Key Laboratory of Chemical Biology of Fujian Province, iChEM, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China.
  • 7 Department of Chemistry and Key Laboratory of Chemical Biology of Fujian Province, iChEM, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China. [email protected].
  • 8 Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China. [email protected].
  • 9 Cancer Hospital, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China. [email protected].
  • 10 Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou, 341000, China. [email protected].
  • 11 Shenzhen Research Institute of Xiamen University, Shenzhen, 518057, China. [email protected].
  • 12 Department of Stem Cell and Regenerative Medicine, International Joint Research Center for Precision Biotherapy, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China. [email protected].
  • 13 Jin-feng Laboratory, Chongqing, 401329, China. [email protected].
  • # Contributed equally.
PMID: 41559402 DOI: 10.1038/s41401-025-01728-y
Abstract

Photodynamic therapy (PDT) boasts the advantages of high spatiotemporal selectivity and non-invasiveness, but its clinical application is still limited by the hypoxic tumor microenvironment and inherent drawbacks of traditional photosensitizers such as aggregation-induced quenching (ACQ), insufficient targeting ability, and systemic toxicity. We previously conducted a structure-activity relationship (SAR) study on a plant-derived alkaloid, berberine, and found that its derivative B12 not only significantly enhanced antitumor efficacy but also improved water solubility and bioavailability. In this study, we characterized the photodynamic properties of B12, investigated its Anticancer mechanisms, and evaluated the photodynamic therapeutic efficacy and biosafety of B12 in the tumors of xenograft mouse models. We showed that B12 was a novel Photosensitizer without ACQ effect, exhibited both type I and type II photodynamic activities, and generated a large amount of Reactive Oxygen Species (ROS) under both normoxic and hypoxic conditions. In addition, B12 (12.5, 25 μM) significantly enhanced its therapeutic effect against RKO and HCT116 cells in the hypoxic microenvironment by inhibiting the Akt/mTOR signaling pathway and downregulating the expression of hypoxia-inducible factor HIF-1α. In RKO cells, B12 (2 μM) exhibited dynamic dual-organelle-targeting properties after photoactivation: it first induced the collapse of mitochondrial membrane potential, then translocated to the nucleus and bound to DNA. It improved the intersystem crossing (ISC) efficiency by narrowing the singlet-triplet energy gap, thereby amplifying the generation of ROS and damaging DNA integrity. In mice xenografted with B16 cells, intratumoral injection of B12 (5 mg/kg) followed by 10 min light irradiation daily for 9 days significantly suppressed tumor growth with good biosafety. In conclusion, the small molecule B12 simultaneously possesses type I and type II photodynamic activities, dynamic organelle-targeting and hypoxia adaptation properties. This study may provide a reference for the research and design of hypoxia-tolerant small-molecule photosensitizers and break through the clinical bottlenecks of photodynamic therapy.

Keywords

HIF-1α; apoptosis; berberine derivatives; colorectal cancer cells; photodynamic therapy; reactive oxygen species.

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