神經膠母細胞瘤是成人中最常見且最惡性之初級腦瘤。儘管病人接受外科手術、放射線、化學藥物等標準治療，其預後依然不佳。由於神經膠母細胞瘤具有高度異質性，使其易建立治療抗性，並成為發展有效治療方式之阻礙。因此，我們利用連續處理放射線與化學藥物Temozolomide (TMZ) 以建立具有放射線抗性與同時具有放射線及TMZ抗性之細胞模式。其中，放射線改變腫瘤細胞之型態、將大電導鈣離子活化型之鉀離子通道 (BK通道) 去活化、促進轉化生長因子TGF-β誘導的間質性分化、及藉由增強乙醛脫氫酶Aldehyde dehydrogenases (ALDH) 以獲得腫瘤幹細胞特性。因此，我們提出之假說為以調控細胞型態之分子為標靶可抑制具有治療抗性的神經膠母細胞瘤。我們探討BK通道、TGF-β與ALDH的交互作用在神經膠母細胞瘤之抗性中扮演的角色與其治療潛力。首先，我們檢視在抗性之細胞模式中，治療抗性之指標因子的變化。我們發現放射線抗性促進Akt之磷酸化、以非p53之方式降低p21之表現、與增強多種藥物抗性蛋白之表現，且放射線抗性造成帝盟多去敏化，並促進細胞增生與細胞遷移之能力。此外，放射線抗性藉由非表現之方式誘導BK通道去活化。在原生的神經膠母細胞瘤中，藉由抑制向外之鉀離子電流、以Paxilline抑制BK通道、或調降BK通道之表現可促進細胞增生與細胞遷移之能力，反之，普達錠Cilostazol可活化BK通道，進而逆轉由放射線抗性誘導之細胞遷移、細胞增生、與腫瘤幹細胞特性。藉由原位腦瘤模式，普達錠Cilostazol可抑制具有放射線抗性的神經膠母細胞瘤之生長，並延長其存活率。另一方面，TGF-β誘導之間質性分化為一癌症惡化進展之指標因子。腫瘤幹細胞之特性可調控自我新生、抗藥性、與分化造成治療抗性。ALDH1為一新型腫瘤幹細胞之指標分子，然而，ALDH1在神經膠母細胞瘤建立抗性中扮演的角色尚不清楚。雙硫崙Disulfiram (DSF) 為治療酗酒之藥物，其作用機制為抑制ALDH之活性。近期亦發現DSF具有抑癌作用，但機制尚未清楚。因此，我們評估共同抑制ALDH與TGF-β訊息傳遞路徑對於具有治療抗性的神經膠母細胞瘤之治療效果。無論是抑制ALDH或專一抑制ALDH1皆可反轉治療抗性誘導之細胞遷移。另外，我們亦選用了抑制TGF-β接受器的專一抑制劑LY364947與標靶藥物Galunisertib以抑制TGF-β訊息路徑。共同抑制ALDH與TGF-β訊息傳遞路徑的治療方式比單一治療方式對於細胞增生、細胞遷移、與腫瘤幹細胞特性有更好的抑制效果。藉由原位腦瘤模式，我們發現單獨使用DSF或Galunisertib不影響腫瘤生長，但DSF搭配Galunisertib具有抑癌效果。而機制探討上，抑制TGF-β接受器可減少原生性與具治療抗性之神經膠母細胞瘤之ALDH活性，然而，外源性的TGF-β僅增加原生性的U87MG細胞之ALDH活性。反之，抑制ALDH活性可降低原生性與具治療抗性的神經膠母細胞瘤分泌TGF-β。DSF可直接減少由治療抗性誘導之的第一型TGF-β接受器、Smad2、轉錄因子Slug之表現，進而減少間質性分化標誌分子之表現。共同抑制TGF-β訊息傳遞與ALDH可逆轉由治療抗性誘導之間質性分化。因此，本研究發現BK通道的去活化可幫助神經膠母細胞瘤建立放射線抗性。另外，ALDH可調控TGF-β所誘導的間質性分化，幫助神經膠母細胞瘤建立治療抗性。根據以上的發現，活化BK通道與共同抑制ALDH與TGF-β訊息傳導路徑可針對復發性的神經膠母細胞瘤之病人，作為的潛力的有效治療策略。

Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults. In spite of receiving the current standard of care including neurosurgery following with radio-, chemo-, and radiochemotherapy, the prognosis remains dismal. Due to high heterogeneity, developing therapeutic resistance is the most difficult obstacle for curing GBM. We have developed the radiation-resistant (RR) and radiation-temozolomide (TMZ)-resistant (RTR) GBM cell models by consecutive irradiation and TMZ treatment. RR altered the cellular morphology, inactivated the big-conductance calcium-activated potassium channel (BK channel), promoted TGF-β-induced mesenchymal differentiation (MD), and acquired cancer stemness by upregulating aldehyde dehydrogenases (ALDHs). Therefore, we hypothesized that targeting on the molecules involved in regulating cellular morphology may treat therapeutic-resistant GBM. We investigated the roles and therapeutic potential of BK channel activity, and the interplay between MD and cancer stemness in GBM resistance. At first, we evaluated the resistant indicators in our model. We found that RR enhanced the phosphorylation of Akt, reduced the expression of p21 in the p53-independent manners, and increased multidrug-resistant proteins. Furthermore, RR resulted in TMZ insensitization, promoted cell mobility, and accelerated proliferation. Also, RR inactivated BK channel in the expression-independent manner. In parental GBM cells, inhibiting outward potassium currents, blocking BK channels by Paxilline or knockdown BK channels promoted cell mobility and proliferation. In contrast, re-evoking BK channel by Cilostazol reversed RR-induced cell migration, proliferation, and cancer stemness. By orthotopic xenograft model, Cilostazol inhibited in vivo growth and improved the survival. In addition, TGF-β signaling-induced MD is a malignant indicator of cancers. Cancer stemness is another major factor in cancer resistance by regulating self-renewal, drug resistance, and differentiation. ALDH1 is a new cancer stem cell marker. However, the role of ALDH in GBM resistance remains unclear. Disulfiram (DSF) is an anti-alcoholism drug by inhibiting ALDH activity. Recently, DSF shows anti-tumor efficacy while the mechanisms/targets remains unknown. Accordingly, we evaluated the therapeutic effects of concurrent TGF-β and ALDH blockade on resistant GBM. Inhibiting pan-ALDH or ALDH1 reversed resistance-induced cell migration. The approved drug Galunisertib targeting TGF-β receptors (TRs) and a TRs inhibitor LY364947 were used to block TGF-β signaling. Combining the inhibition of TGF-β signaling and ALDH showed higher inhibitory effects on cell growth, motility, and cancer stemness than sole treatments. By orthotopic xenograft GBM model, combining Galunisertib and DSF showed anti-tumor effects while sole DSF and Galunisertib did not affect tumor growth. Mechanistically, inhibiting TGF-β signaling attenuated ALDH activity in parental and resistant GBM cells. However, exogenous TGF-β only increased ALDH activity in parental U87MG cells. In parallel, inhibiting ALDHs attenuated TGF-β secretion in parental and resistant GBM cells. DSF directly reduced the resistance-induced expression of TRI, Smad2, Slug, and mesenchymal markers. Combining the inhibition of TGF-β signaling and ALDH reversed resistance-induced MD. Based on the above findings, the inactivation of the BK channel was able to assist GBM in developing RR. Also, ALDH conferred GBM resistance via regulating TGF-β-induced MD. Therefore, re-activating BK channels and concurrent inhibition of ALDH and TGF-β signaling may be the good therapeutic strategies for recurrent GBM patients.

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