<sup>18</sup>F-Berberine Derivatives: a Potential Molecular Imaging Agent for Tumor Targeting by PET/CT Tumor_Journal of Biomedical Engineering

Authors：

MEIXiaoli ^1,2 , WUXiaoai ¹ , ZHANGTong ¹ , LIANGMeng ¹ ,  FANChengzhong ¹

1. Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu 610041, China;
2. Department of Nuclear Medicine, First Affiliated Hospital, Zhengzhou University, Zhengzhou 450000, China;

Corresponding author：

FANChengzhong, Email: Chengzhong.fan@scu.edu.cn

Keywords：

¹⁸Fluorine; berberine derivatives; tumor; PET/CT; molecular imaging

DOI：

10.7507/1001-5515.20150083

Video：

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Cancer is one of the main causes of death for human beings. Clinical oncologists increasingly rely upon imaging for diagnosis, stage, response assessment, and follow-up in cancer patient. However, ¹⁸F-FDG is not a tumor specific agent, inflammation and infection also have intensive uptake of ¹⁸F-FDG, resulting in false positive diagnosis, and some tumors have low uptake of ¹⁸F-FDG or even do not uptake ¹⁸F-FDG, leading to false negative diagnosis. So it is urgent to develop non-¹⁸F-FDG novel tumor targeting agent. Recently, a large number of researches in vitro have demonstrated that berberine has anti-tumor activity against a variety of tumor cells by inducing tumor cell apoptosis through inhibition of mitochondrial respiratory chain etc. So far, there is no credible evidence of berberine targeting in tumor in vivo. We proposed a hypothesis that berberine has the characteristics of tumor targeting biodistribution in vivo, and verified the proposal by ¹⁸F-berberine PET/CT imaging in VX2 muscle tumor-bearing rabbit model. In this review, we intend to give an overview of the progress of berberine anticancer, the structural bases of berberine anticancer and the uderlying molecular mechanisms of berberine anticancer indentified so far. We also introduce the first visualization of ¹⁸F labeled berberine derivatives targeting tumor in VX2 muscle tumor-bearing rabbit model by PET/CT. These breakthrough findings suggest that ¹⁸F-berberine derivatives as a potential PET/CT tumor targeted molecular imaging agent may have important implications for cancer targeting therapy, molecular imaging and modernization of Traditional Chinese Medicine.

Citation： MEIXiaoli, WUXiaoai, ZHANGTong, LIANGMeng, FANChengzhong. ¹⁸F-Berberine Derivatives: a Potential Molecular Imaging Agent for Tumor Targeting by PET/CT Tumor. Journal of Biomedical Engineering, 2015, 32(2): 460-464. doi: 10.7507/1001-5515.20150083 Copy

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15.	PEREIRA G C, BRANCO A F, MATOS J A, et al. Mitochondrially targeted effects of berberine[Natural Yellow 18, 5, 6-dihydro-9, 10-dimethoxybenzo(g)-1, 3-benzodioxolo(5, 6-a) quinolizinium] on K1735-M2 mouse melanoma cells:comparison with direct effects on isolated mitochondrial fractions[J]. J Pharmacol Exp Ther, 2007, 323(2):636-649.
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26.	WU K, YANG Q, MU Y, et al. Berberine inhibits the proliferation of colon cancer cells by inactivating Wnt/β-catenin signaling[J]. Int J Oncol, 2012, 41(1):292-298.
27.	MA C, TANG K, LIU Q, et al. Calmodulin as a potential target by which berberine induces cell cycle arrest in human hepatoma Bel7402 cells[J]. Chem Biol Drug Des, 2013, 81(6):775-783.
28.	MEI X, WU X, FAN C, et al. Radiosynthesis of novel 18f-berberine derivatives as potential tumor imaging agent[J]. J Nucl Med, 2012, 53(Suppl 1):S337.
29.	SEGALL G, DELBEKE D, STABIN M G, et al. SNM practice guideline for Sodium ¹⁸F-fluoride PET/CT bone scans 1.0[J]. J Nucl Med, 2010, 51(11):1813-1820.

1. HISTED S N, LINDENBERG M L, MENA E, et al. Review of functional/anatomical imaging in oncology[J]. Nucl Med Commun, 2012, 33(4):349-361.
2. SAGA T, KOIZUMI M, FURUKAWA T, et al. Molecular imaging of cancer:evaluating characters of individual Cancer by PET/SPECT imaging[J]. Cancer Sci, 2009, 100(3):375-381.
3. ZHU A, LEE D, SHIM H. Metabolic PET imaging in cancer detection and therapy response[J]. Semin Oncol, 2011, 38(1):55-69.
4. BEYER T, TOWNSEND D W, CZERNIN J, et al. The future of hybrid imaging-part 2:PET/CT[J]. Insights into Imaging, 2011, 2(3):225-234.
5. NATOLI C, RAMAZZOTTI V, NAPPI O, et al. Unknown primary tumors[J]. Biochim Biophys Acta, 2011, 1816(1):13-24.
6. MOLLER A K, LOFT A, BERTHELSEN A K, et al. ¹⁸F-FDG PET/CT as a diagnostic tool in patients with extracervical carcinoma of unknown primary site:a literature review[J]. Oncologist, 2011, 16(4):445-451.
7. PALMA M D, GREGIANIN M, FIDUCCIA P, et al. PET/CT imaging in gynecologic malignancies:a critical overview of its clinical impact and our retrospective single center analysis[J]. Critical Reviews in Oncology/hematology, 2012, 83(1):84-98.
8. LONG N M, SMITH C S. Causes and imaging features of false positives and false negatives on F-PET/CT in oncologic imaging[J]. Insights into Imaging, 2011, 2(6):679-698.
9. DIOGO C V, MACHADO N G, BARBOSA I A, et al. Berberine as a promising safe anti-cancer agent-is there a role for mitochondria?[J]. Curr Drug Targets, 2011, 12(6):850-859.
10. SCATENA R. Mitochondria and cancer:a growing role in apoptosis. cancer cell metabolism and dedifferentiation[J]. Adv Exp Med Biol, 2012, 942:287-308.
11. PINTO-GARCIA L, EFFERTH T, TORRES A, et al. Berberine inhibits cell growth and mediates caspase-independent cell death in human pancreatic cancer cells[J]. Planta Med, 2010, 76(11):1155-1161.
12. SINGH I P, MAHAJAN S. Berberine and its derivatives:a patent review(2009-2012)[J]. Expert Opin Ther Patents, 2013, 23(2):215-231.
13. CHIDAMBARA MURTHY K N, JAYAPRAKASHA G K, PATIL B S. The natural alkaloid berberine targets multiple pathways to induce cell death in cultured human colon cancer cells[J]. Eur J Pharmacol, 2012, 688(1-3):14-21.
14. PEREIRA C V, MACHADO N G, OLIVEIRA P J. Mechanisms of berberine (natural yellow 18)-induced mitochondrial dysfunction:interaction with the adenine nucleotide translocator[J]. Toxicol Sci, 2008, 105(2):408-417.
15. PEREIRA G C, BRANCO A F, MATOS J A, et al. Mitochondrially targeted effects of berberine[Natural Yellow 18, 5, 6-dihydro-9, 10-dimethoxybenzo(g)-1, 3-benzodioxolo(5, 6-a) quinolizinium] on K1735-M2 mouse melanoma cells:comparison with direct effects on isolated mitochondrial fractions[J]. J Pharmacol Exp Ther, 2007, 323(2):636-649.
16. LI-WEBER M. Targeting apoptosis pathways in cancer by Chinese medicine[J]. Cancer Lett, 2013, 332(2):304-312.
17. XU L N, LU B N, HU M M, et al. Mechanisms involved in the cytotoxic effects of berberine on human colon cancer HCT-8 cells[J]. Biocell, 2012, 36(3):113-120.
18. LI J, GU L, ZHANG H, et al. Berberine represses DAXX gene transcription and induces cancer cell apoptosis[J]. Lab Invest, 2013, 93(3):354-364.
19. YE H, YE L, KANG H, et al. HIT:linking herbal active ingredients to targets[J]. Nucleic Acids Res, 2011, 39(Database issue):1055-1059.
20. TILLHON M, GUAMÁN ORTIZ L M, LOMBARDI P, et al. Berberine:new perspectives for old remedies[J]. Biochem Pharmacol, 2012, 84(10):1260-1267.
21. YIP N K, HO W S. Berberine induces apoptosis via the mitochondrial pathway in liver cancer cells[J]. Oncol Rep, 2013, 30(3):1107-1112.
22. YANG X, HUANG N. Berberine induces selective apoptosis through the AMPK-mediated mitochondrial/caspase pathway in hepatocellular carcinoma[J]. Mol Med Report, 2013, 8(2):505-510.
23. WANG L, CAO H, LU N, et al. Berberine inhibits proliferation and down-regulates epidermal growth factor receptor through activation of Cbl in colon tumor cells[J]. PLoS One, 2013, 8(2):e56666.
24. WANG L, LIU L, SHI Y, et al. Berberine induces caspase-independent cell death in colon tumor cells through activation of apoptosis-inducing factor[J]. PLoS One, 2012, 7(5):e36418.
25. WANG Y, LIU Q, LIU Z, et al. Berberine, a genotoxic alkaloid, induces ATM-Chk1 mediated G2 arrest in prostate Cancer cells[J]. Mutat Res, 2012, 734(1-2):20-29.
26. WU K, YANG Q, MU Y, et al. Berberine inhibits the proliferation of colon cancer cells by inactivating Wnt/β-catenin signaling[J]. Int J Oncol, 2012, 41(1):292-298.
27. MA C, TANG K, LIU Q, et al. Calmodulin as a potential target by which berberine induces cell cycle arrest in human hepatoma Bel7402 cells[J]. Chem Biol Drug Des, 2013, 81(6):775-783.
28. MEI X, WU X, FAN C, et al. Radiosynthesis of novel 18f-berberine derivatives as potential tumor imaging agent[J]. J Nucl Med, 2012, 53(Suppl 1):S337.
29. SEGALL G, DELBEKE D, STABIN M G, et al. SNM practice guideline for Sodium ¹⁸F-fluoride PET/CT bone scans 1.0[J]. J Nucl Med, 2010, 51(11):1813-1820.

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¹⁸F-Berberine Derivatives: a Potential Molecular Imaging Agent for Tumor Targeting by PET/CT Tumor

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¹⁸F-Berberine Derivatives: a Potential Molecular Imaging Agent for Tumor Targeting by PET/CT Tumor