多型性神經膠質母細胞瘤（glioblastoma multiforme, GBM）是最常見的原發性腦瘤，它的高度侵略性使GBM成為預後不良以及復發率高的疾病。傳統的治療為手術輔以放射線及化療為主，但並無法有效根治。目前主要化療藥物Temozolomide (TMZ)在初期可以有效的抑制腦癌細胞的存活率，但因病人常對TMZ產生抗藥性，因此科學家們還在積極尋找其他具有療效的化療藥物。已經有許多研究指出，在癌細胞中之癌幹細胞（cancer stem cells, CSCs）具有特殊蛋白質通道能將化療藥物排出細胞外，對癌症的抗藥性及復發都有很大的關聯性。為了找出可以有效抑制腦癌幹細胞生長的藥物，我們檢測吲哚類的化合藥物是否能夠抑制腦癌類癌幹細胞的增殖。結果顯示Gavin 08可以有效降低腦癌類幹細胞的增殖能力使細胞週期停滯，並且促進細胞凋亡。因此，我們認為Gavin 08可以降低腦癌細胞的增殖與存活，具成為新穎化療藥物的潛力。

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Its aggressiveness makes it a malignant disease with poor prognosis and high recurrence. Neither surgical resection nor traditional chemotherapeutic drugs are effective treatments for this disease., The major chemotherapy drug is Temozolomide (TMZ) currently. Although TMZ effectively inhibits the survival rate of glioblastoma cell line in the beginning of the treatment, patients often develop drug resistance soon. Therefore, scientists constantly search for new chemotherapeutic drugs. Many studies have reported that the cancer stem cells (CSCs) in the tumor mass have the special protein channels that can excrete chemotherapeutic drugs out of the cancer stem cell. Thus, CSCs may have strong correlation with cancer recurrence and drug resistance. To screen new therapeutic compounds that effectively inhibit CSCs of GBM, we examined the proliferation inhibition ability of indole compounds for GBM. The results revealed that the chemical compound, Gavin 08, can reduce the cell proliferation and promote the apoptosis of GSCs. In summary, Gavin 08 may be a potential novel chemotherapeutic drug for targeting glioblastoma stem cell.

1. Jovcevska, I., N. Kocevar, and R. Komel, Glioma and glioblastoma - how much do we (not) know? Mol Clin Oncol, 2013. 1(6): p. 935-941.
2. Okada, H., et al., Immunotherapeutic approaches for glioma. Critical Reviews™ in Immunology, 2009. 29(1): p. 1-42.
3. Bleeker, F.E., R.J. Molenaar, and S.J.J.o.n.-o. Leenstra, Recent advances in the molecular understanding of glioblastoma. 2012. 108(1): p. 11-27.
4. DeAngelis, L.M., Brain tumors. New England Journal of Medicine, 2001. 344(2): p. 114-123.
5. Young, R.M., et al., Current trends in the surgical management and treatment of adult glioblastoma. 2015. 3(9).
6. Walker, M.D., et al., Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: a cooperative clinical trial. Journal of neurosurgery, 1978. 49(3): p. 333-343.
7. Fukushima, T., H. Takeshima, and H.J.A.r. Kataoka, Anti-glioma therapy with temozolomide and status of the DNA-repair gene MGMT. 2009. 29(11): p. 4845-4854.
8. Zhang, J., M. FG Stevens, and T. D Bradshaw, Temozolomide: mechanisms of action, repair and resistance. Current molecular pharmacology, 2012. 5(1): p. 102-114.
9. Batich, K.A., et al., Long-term survival in glioblastoma with cytomegalovirus pp65-targeted vaccination. 2017. 23(8): p. 1898-1909.
10. Rahman, M., et al., The role of CMV in glioblastoma and implications for immunotherapeutic strategies. Oncoimmunology, 2019. 8(1): p. e1514921.
11. Moharil, R.B., et al., Cancer stem cells: An insight. J Oral Maxillofac Pathol, 2017. 21(3): p. 463-468.
12. Begicevic, R.R. and M. Falasca, ABC Transporters in Cancer Stem Cells: Beyond Chemoresistance. Int J Mol Sci, 2017. 18(11).
13. Ballabh, P., A. Braun, and M. Nedergaard, The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis, 2004. 16(1): p. 1-13.
14. van de Waterbeemd, H., et al., Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors. Journal of drug targeting, 1998. 6(2): p. 151-165.
15. Wang, D., et al., A comprehensive review in improving delivery of small-molecule chemotherapeutic agents overcoming the blood-brain/brain tumor barriers for glioblastoma treatment. Drug Delivery, 2019. 26(1): p. 551-565.
16. Moharil, R.B., et al., Cancer stem cells: An insight. 2017. 21(3): p. 463.
17. Glumac, P.M. and A.M. LeBeau, The role of CD133 in cancer: a concise review. Clin Transl Med, 2018. 7(1): p. 18.
18. Garros-Regulez, L., et al., Targeting SOX2 as a Therapeutic Strategy in Glioblastoma. Front Oncol, 2016. 6: p. 222-228.
19. Song, W.S., et al., Sox2, a stemness gene, regulates tumor-initiating and drug-resistant properties in CD133-positive glioblastoma stem cells. J Chin Med Assoc, 2016. 79(10): p. 538-45.
20. Polyak, K. and R.A. Weinberg, Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nature Reviews Cancer, 2009. 9(4): p. 265-273.
21. Liu, Q., et al., Berberine induces senescence of human glioblastoma cells by downregulating the EGFR-MEK-ERK signaling pathway. Mol Cancer Ther, 2015. 14(2): p. 355-63.
22. Li, Y., et al., Cytotoxic Indole Alkaloid 3alpha-Acetonyltabersonine Induces Glioblastoma Apoptosis via Inhibition of DNA Damage Repair. Toxins (Basel), 2017. 9(5): p. 1-17.
23. Pajouhesh, H. and G.R. Lenz, Medicinal chemical properties of successful central nervous system drugs. NeuroRx, 2005. 2(4): p. 541-553.
24. Kansy, M., F. Senner, and K. Gubernator, Physicochemical high throughput screening: parallel artificial membrane permeation assay in the description of passive absorption processes. Journal of medicinal chemistry, 1998. 41(7): p. 1007-1010.
25. Podhorecka, M., A. Skladanowski, and P. Bozko, H2AX Phosphorylation: Its Role in DNA Damage Response and Cancer Therapy. J Nucleic Acids, 2010. 2010.
26. Cheng, F. and D. Guo, MET in glioma: signaling pathways and targeted therapies. J Exp Clin Cancer Res, 2019. 38(1): p. 270.
27. Thiery, J.P., et al., Epithelial-mesenchymal transitions in development and disease. Cell, 2009. 139(5): p. 871-90.
28. Brabletz, T., et al., EMT in cancer. Nat Rev Cancer, 2018. 18(2): p. 128-134.
29. Campbell, K. and J. Casanova, A common framework for EMT and collective cell migration. Development, 2016. 143(23): p. 4291-4300.
30. Herbst, R.S., Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys, 2004. 59(2 Suppl): p. 21-6.
31. Westphal, M., C.L. Maire, and K. Lamszus, EGFR as a Target for Glioblastoma Treatment: An Unfulfilled Promise. CNS Drugs, 2017. 31(9): p. 723-735.
32. Zandi, R., et al., Mechanisms for oncogenic activation of the epidermal growth factor receptor. Cell Signal, 2007. 19(10): p. 2013-23.
33. Mendelsohn, J., Blockade of receptors for growth factors: an anticancer therapy—the fourth annual Joseph H. Burchenal American Association for Cancer Research Clinical Research Award Lecture. Clinical Cancer Research, 2000. 6(3): p. 747-753.
34. Lamoral-Theys, D., et al., Lycorine, the main phenanthridine Amaryllidaceae alkaloid, exhibits significant antitumor activity in cancer cells that display resistance to proapoptotic stimuli: an investigation of structure-activity relationship and mechanistic insight. J Med Chem, 2009. 52(20): p. 6244-56.
35. Ying, X., et al., Lycorine inhibits breast cancer growth and metastasis via inducing apoptosis and blocking Src/FAK-involved pathway. Sci China Life Sci, 2017. 60(4): p. 417-428.
36. Shen, J., et al., Lycorine inhibits glioblastoma multiforme growth through EGFR suppression. J Exp Clin Cancer Res, 2018. 37(1): p. 157.
37. Hu, M., et al., Lycorine is a novel inhibitor of the growth and metastasis of hormone-refractory prostate cancer. Oncotarget, 2015. 6(17): p. 15348.