中文摘要
本論文探討了氧化鍺(GeO2)的生物效應。鍺化合物在分子及細胞層次上的

研究在過去甚少被討論。本研究的第一部分探討了氧化鍺在細胞週期上的效

應。氧化鍺對中國倉鼠卵巢(CHO)細胞並無基因毒性，而細胞毒性也很有限。然

而，氧化鍺卻會使細胞停滯在G2/M 時期。當氧化鍺處理時間為12小時劑量在

5 mM以下時，停滯在G2/M 時期的細胞群會隨著氧化鍺劑量的增加而增加，但

在氧化鍺劑量高於5 mM 以上時，停滯在G2/M 時期的細胞群則會降低。由

5-bromodeoxyuridine 標定的細胞之分析指出，氧化鍺會依劑量的增加而延遲S

phase之進行，並且將細胞阻擋在G2/M時期。由共軛焦顯微鏡的觀察證實了氧

化鍺處理確實會將細胞停滯在G2時期。與其他會引起G2 停滯之情況相類似的

是，氧化鍺所引起G2 停滯的情形也可被caffeine 依劑量及處理時間增加而解

除。為了探究氧化鍺所引發G2停滯之機制，我們檢測了cyclin的量以及與cyclin

有關的kinase之活性。在CHO細胞中，cyclin B1的量在氧化鍺處理後並不受影

響。然而，氧化鍺卻會降低p34cdc2 kinase (Cdk1)的活性。此kinase的活性在氧化

鍺移除後9小時內會恢復，並且與細胞由G2/M 時期到G1時期的轉換有關。這

些結果指出，氧化鍺處理在CHO 細胞中會降低Cdk1 的活性並且造成細胞停滯

G2時期。

在本論文的第二部分，我們探討了氧化鍺與輻射照射合併處理對CHO 細胞存活的效應。細胞先以0到22 mM的氧化鍺處理12小時之後，再加以輻射照射。合併處理造成細胞之存活率會因氧化鍺的增加而降低並且在細胞毒性上可

觀察到相乘性的效應。細胞存活曲線顯示出，以50%細胞死亡點而言，在加入5

及15 mM氧化鍺之情況下，細胞的輻射敏感性分別增加為2.3及2.75倍。而氧

化鍺不論在輻射照射前4 小時加入或在輻射照射後立刻加入都會增加細胞的輻

射敏感性。氧化鍺並不會影響整體soluble thiol 的量或catalase 和glutathione

S-transferase 的活性。由ROS 生成之分析指出，合併處理會顯著的增加ROS 的

生成量。而加入20 mM抗氧化劑NAC會減低細胞中ROS的生成量。然而，在

氧化鍺及輻射照射處理之後，NAC 卻只能少量的提高細胞存活率。因此，ROS

的生成可能對細胞的死亡只有部分的效果。而氧化鍺及輻射照射合併處理卻是

大量的增加DNA雙股斷裂的情形。而氧化鍺的作用也會降低DNA修復的效率。

綜合而言，合併氧化鍺及輻射照射的處理，可增加DNA之雙股斷裂及細胞死亡。

在本論文的第三部分，我們探討氧化鍺在血緣性細胞HL-60所造成細胞凋

亡之效應。將細胞以5至22 mM 氧化鍺處理24小時後(30%的存活率)，以流式

細胞儀分析發現會造成細胞週期G2/M 時期的停滯並伴隨著sub-G1 比例的上

升。利用電泳分析DNA fragmentation 以及流式細胞儀分析FITC 螢光標示

Annexin-V偵測phosphatidylserine(PS)的外翻證明了氧化鍺所造成的sub-G1比例

是細胞凋亡的細胞。此細胞凋亡可被廣效性的caspase抑制劑，z-VAD-fmk 所抑

制。氧化鍺處理細胞所造成的細胞凋亡過程中，粒線體的功能會受到影響，包

括ROS、粒線體膜電位及Bax/Bcl-XL 比例的增加。同時會造成細胞質中

cytochrome C 及AIF的表現量增加。這些現象都與caspase的活性不相關。然而cytochrome c 的釋出會造成caspase-3 被活化並將其受質PARP 裂解造成細胞凋

亡。此外，氧化鍺會誘發ERK、p38及JNK MAPK活性，經與抑制劑PD98059

及SB203580 合併處理發現，PD98059 抑制ERK 訊號路徑會增加細胞凋亡，而

SB203580 則無此效應。由此推測，氧化鍺誘發ERK與JNK 的活性，JNK活化

可能參與氧化鍺誘發之細胞凋亡，而ERK的活化則是幫助細胞的存活。

Abstract
The biological function of germanium oxide (GeO2) was investigated in this

study. The function of germanium compounds at molecular and cellular levels are

rarely investigated. In the first part, the effect of GeO2 on cell cycle progression was

investigated. GeO2 is not genotoxic to Chinese hamster ovary (CHO) cells and has

limited cytotoxicity. However, GeO2 arrests cells at G2/M phase. The proportion of

cells stopped at G2/M phase increased dose-dependently from 0 to 5 mM GeO2,for

12 h but decreased at GeO2 concentration was greater than 5 mM. Analysis of

5-bromodeoxyuridine-labeled cells indicated that GeO2 delayed S phase progression

in a dose-dependent manner, and blocked cells at G2/M phase. Confocal microscopic

examination confirmed that GeO2 treatment arrested cells at G2 phase. Similar to

several other events that cause G2 block, the GeO2-induced G2 block can also be

ameliorated by caffeine in a dose- and time-dependent manner. To explore the

mechanism of G2 arrest by GeO2, cyclin content and cyclin-dependent kinase activity

were examined. Cyclin B1 level was not affected after GeO2 treatment in CHO cells.

However, GeO2 decreased p34cdc2 kinase (Cdk1) activity. The kinase activity

recovered within 9 h after GeO2 removal and correlated with the transition of G2/M

to G1 phase of the cells. This result suggests that GeO2 treatment reduces Cdk1

activity and causing the G2 arrest in CHO cells.

In the second part, we investigated here the combined effect of GeO2 andradiation on cell viability. Cells were treated with 0 to 22 mM GeO2 for 12 h

followed by 1 Gy X-irradiation. A synergistic cytotoxic effect was observed for the

combined treatment with a dose dependent reduction of cell viability. Complete

survival curves showed a 2.3- and 2.75-fold increase in radiosensitivity for 50% cell

death in the presence of 5 and 15 mM GeO2, respectively. The increased

radiosensitivity also occurred when GeO2 was given either 4 h prior to radiation or

immediately after radiation exposure. GeO2 did not affect total soluble thiol content

or the activities of catalase and glutathione S-transferase. Analysis of the production

of reactive oxygen species (ROS) revealed that the combined treatment dramatically

increased the synthesis of the ROS. Addition of N-acetyl cysteine (NAC, 20 mM)

decreased the ROS production in cells. NAC, however, only slightly increased cell

viability after GeO2 and radiation exposures. Thus, increased ROS production may

partly, if at all, attribute to cell death. The combination of GeO2 and X-irradiation,

however, significantly increased DNA double-strand-break (dsb) frequency. Notably,

the presence of GeO2 also reduced the efficiency of DNA repair. We conclude that

treatment with GeO2 followed by X-irradiation increases DNA dsb and cell death.

In the third part, we investigated the apoptotic effect of GeO2 on hematogenic

cells, HL-60. When cells were treated with 5 to 22 mM GeO2 for 24h, a G2/M arrest

was observed. Additionally, sub-G1 fraction (apoptotic cells) increased with

increasing concentrations of GeO2 as analyzed by flow cytometry, using agarose gelelectrophoresis and FITC-labeled annexine-V to analyze the GeO2-treated cells, a

similar result was found as that of flow cytometry. The apoptotic effect can be

reduced by caspase inhibitor, z-VAD-fmk. For the GeO2-induced apoptosis, increase

of ROS, mitochondrial membrane potential, ratio of Bax/Bcl-XL were noted. Besides,

the level of cytosolic cytochrome c and apoptotic-inducing factor also elevated.

These increased were caspase-independent because z-VAD-fmk could not reverse the

results. However, caspase-3 was activated and caused the cleavage of PARP and

resulted in apoptosis. Treatment of GeO2 activate the ERK, p38 and JNK. The

inhibitor of ERK, PD98059, stimulated the GeO2-induced apoptosis while the p38

inhibitor, SB203580 had no effect. This result shows that JNK may be involved in the

GeO2-induced apoptosis and ERK protects from cell death in the process.

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