Research on the molecular mechanism of a novel naphthalimide derivative 8c inducing apoptosis in multidrug resistant colon cancer cells

王子元; 殷佩浩; 许建华

doi:10.3969/j.issn.1007-3969.2015.05.005

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Research on the molecular mechanism of a novel naphthalimide derivative 8c inducing apoptosis in multidrug resistant colon cancer cells

更新时间：2025-12-31

- Research on the molecular mechanism of a novel naphthalimide derivative 8c inducing apoptosis in multidrug resistant colon cancer cells
- China Oncology Vol. 25, Issue 5, Pages: 345-351(2015)
- 作者机构：
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- DOI：10.3969/j.issn.1007-3969.2015.05.005
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- Published Online：11 August 2015，
  
  Published：11 August 2015
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王子元,殷佩浩,许建华,等. 上海中医药大学附属普陀医院实验中心，上海中医药大学中西医结合肿瘤介入研究所，上海200062[J]. 中国癌症杂志, 2015, 25(5): 345-351.

王子元, 殷佩浩, 许建华. Research on the molecular mechanism of a novel naphthalimide derivative 8c inducing apoptosis in multidrug resistant colon cancer cells[J]. China Oncology, 2015, 25(5): 345-351.
王子元,殷佩浩,许建华,等. 上海中医药大学附属普陀医院实验中心，上海中医药大学中西医结合肿瘤介入研究所，上海200062[J]. 中国癌症杂志, 2015, 25(5): 345-351. DOI： 10.3969/j.issn.1007-3969.2015.05.005.

王子元, 殷佩浩, 许建华. Research on the molecular mechanism of a novel naphthalimide derivative 8c inducing apoptosis in multidrug resistant colon cancer cells[J]. China Oncology, 2015, 25(5): 345-351. DOI： 10.3969/j.issn.1007-3969.2015.05.005.

摘要

背景与目的：细胞凋亡受阻是肿瘤细胞产生耐药的重要因素，从细胞凋亡的研究入手，将为肿瘤的治疗和耐药性的逆转开辟新的途径。本研究观察一种新型萘酰亚胺类衍生物8c对结肠癌HCT116/L-OHP耐药细胞的作用，探讨诱导HCT116/L-OHP耐药细胞凋亡的分子机制。方法：采用CCK-8法检测8c对HCT116/L-OHP细胞的增殖抑制作用；采用流式细胞术观察8c对HCT116/L-OHP细胞凋亡的影响；采用实时定量PCR(realtime PCR)检测p53 mRNA、Bax mRNA及Bcl-2 mRNA水平变化；蛋白［质］印迹法(Western blot)检测p-p53、Bax、Bcl-2及细胞色素c(Cyt-c)的蛋白表达水平。结果：8c抑制HCT116/L-OHP细胞增殖的半数抑制浓度(IC

=8.16 μmol/L)低于阳性对照氨奈菲特(IC

=28.37 μmol/L)；药物作用后，8c诱导耐药细胞产生凋亡，凋亡通路中p53(Ser15)磷酸化水平上升，但p53 mRNA水平不受影响；Bax蛋白水平及mRNA水平明显上升，Bcl-2蛋白及mRNA水平下降，使得Bax/Bcl-2比例增加，同时8c又引起细胞色素c的释放。结论：8c通过磷酸化p53 Ser-15位点激活p53，随即激活细胞凋亡通路相关蛋白的表达，这可能是8c抑制结肠癌HCT116/L-OHP耐药细胞增殖的重要机制之一。8c具有良好的抗肿瘤及抗耐药潜力和开发应用前景。

Abstract

Background and purpose: Suppression of apoptotic signaling pathways is an important factor in tumor cell resistance. Research on cell apoptosis will open up a new way of reversing drug resistance and tumor treatment. This study examined the effects of a novel naphthalimide derivative 8c on multidrug resistant colon cancer HCT116/L-OHP cells and explored the molecular mechanisms underlying the apoptosis induction. Methods: The anti-proliferative effects of 8c were detected by CCK-8 assays and the ef

fects on apoptosis induction were examined by flow cytometry. The mRNA expression levels of p53

Bax and Bcl-2 were measured by real-time PCR; The protein expressions of p-p53

Bax

Bcl-2 and Cyt-c were detected by Western blot. Results: 8c (IC

=8.16 μmol/L) seemed to be more potent than amonafide (IC

=28.37 μmol/L) against HCT116/L-OHP cells. 8c induced apoptosis on HCT116/ -OHP cell lines through intrinsic or mitochondria dependent pathway. The protein expression of phosphorylation of p53 at Ser-15 was increased

but the mRNA level of p53 did not increase in HCT116/L-OHP cells. Bax protein and mRNA levels were significantly increased

and Bcl-2 protein and mRNA levels were decreased

suggesting an increase of Bax/Bcl-2 ratios. Meanwhile

8c induced a substantial release of cytochrome c from the mitochondria into the cytosol in HCT116/L-OHP cells. Conclusion: 8c nduced cell death signal by inducing the activation p53 phosphorylation which subsequently activated related protein expressions of apoptotic pathway

which may be an important mechanism of 8c on inhibiting proliferation of HCT116/L-OHP resistant cells. All the results suggested that 8c was a potent compound to be developed as an anti-tumor and anti-resistance agent for clinic application in the future.

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