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Induction of aldehydic DNA lesions in human breast cancer cell line T-47D by quinonoid derivitives of naphthalene
本研究之主要目的為探討萘之醌類代謝物1,2-dihydroxynaphthalene(NCAT)及1,4-dihydroxynaphthalene(NHQ)能否經由細胞內之氧化還原循環，進而生成活性氧化物(reactive oxygen species, ROS)誘發人類乳癌細胞T-47D核酸醛基損害(aldehydic DNA lesion, ADL)及其生成之機制。研究結果顯示，NCAT可以誘發人類乳癌細胞T-47D ADL 之生成，且與細胞反應1.5小時後ADL生成量與控制組相較達到最大值(p<0.001)，但延長反應時間(至8 — 16 小時)，此一細胞核酸損壞作用即回覆正常(p>0.05)。但測試細胞移除NCAT所誘發之ADL之DNA修補效率實驗發現，即是經更新培養液之細胞，經過6.5小時再培養(post-incubation)，其所誘發之ADL依舊存在(p<0.05)。此一研究結果顯示，可能為NCAT誘發氧化壓力進而促進核酸修補酵素之基因表現所致。若比較NCAT及NHQ誘發細胞之ADL能力的差異，研究結果顯示，NCAT (750μM及1.25 mM)可以誘發ADL之生成且為concentration-dependent，反之，NHQ於相同濃度下並無法有效誘發ADL的生成，但此一誘發細胞核酸損壞作用之研究結果，與SRB細胞存活率測試結果相異，亦即NHQ對人類T47D細胞之毒性較NCAT為強。而利用putrescine-cleavage assay確認由NCAT所誘發的ADL大部分為氧化壓力所致。進一步之研究結果發現，過渡性金屬離子Cu (Ⅰ)、Fe(Ⅱ)、及 過氧化氫參與NCAT誘發ADL的機制。
The primary purpose of this research is to examine the potentials of the induction aldehydic DNA lesions (ADL) by quinonoid derivatives of naphthalene, e.g., 1,2-dihydroxynaphthalene (NCAT), 1,4-dihydroxynaphthalene (NHQ) in human T-47D breast cancer cell line. Results indicated that when cells treated with NCAT (1 mM, 2 h), increases in the number of ADL was detected in T-47D cells exposed to NCAT for 1.5 h (p<0.001). When cells exposed to NCAT for additional 6 — 14h, no significant increases in the number of ADL was detected when compared to the corresponding control (p>0.05). In contrast, increases in the number of ADL were detected in cells treated with NCAT for 1.5 h followed by incubation with fresh medium for additional 6.5 h (p<0.05). These findings suggest that NCAT may induce ROS-mediated induction of the expression of BER genes to excise this type of DNA lesions with efficiency in cells. Although NHQ did not induce appreciable increases in the number of ADL when compared to control (p>0.05), NHQ is more toxic than NCAT toward human T47D cells as assayed by SRB assay. Further investigation indicated that the ADL induced by NCAT contain predominantly (100%) putrescine-excisable ADL in T-47D cells. Futher, iron (II) copper (I), hydrogen peroxide participate in the induction of ADL by NCAT in T-47D cells. Overall, this evidence confirmed that the ADL induced by NCAT in T-47D cells is derived from oxidative events.
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