Research Department of Surgical Biotechnology, Division of Surgery and Interventional Science, University College London, London, NW3 2PF, UK.
Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, NW3 2PF, UK.
Sci Rep. 2020 Mar 9;10(1):4363. doi: 10.1038/s41598-020-61381-9.
Doxycycline has anti-tumour effects in a range of tumour systems. The aims of this study were to define the role mitochondria play in this process and examine the potential of doxycycline in combination with gemcitabine. We studied the adenocarcinoma cell line A549, its mitochondrial DNA-less derivative A549 ρ° and cultured fibroblasts. Treatment with doxycycline for 5 days resulted in a decrease of mitochondrial-encoded proteins, respiration and membrane potential, and an increase of reactive oxygen species in A549 cells and fibroblasts, but fibroblasts were less affected. Doxycycline slowed proliferation of A549 cells by 35%. Cellular ATP levels did not change. Doxycycline alone had no effect on apoptosis; however, in combination with gemcitabine given during the last 2 days of treatment, doxycycline increased caspase 9 and 3/7 activities, resulting in a further decrease of surviving A549 cells by 59% and of fibroblasts by 24% compared to gemcitabine treatment alone. A549 ρ° cells were not affected by doxycycline. Key effects of doxycycline observed in A549 cells, such as the decrease of mitochondrial-encoded proteins and surviving cells were also seen in the cancer cell lines COLO357 and HT29. Our results suggest that doxycycline suppresses cancer cell proliferation and primes cells for apoptosis by gemcitabine.
强力霉素在多种肿瘤系统中具有抗肿瘤作用。本研究旨在确定线粒体在该过程中的作用，并研究强力霉素与吉西他滨联合应用的潜力。我们研究了腺癌细胞系 A549、其线粒体 DNA 缺失的衍生物 A549 ρ°和培养的成纤维细胞。用强力霉素处理 5 天导致 A549 细胞和成纤维细胞中线粒体编码蛋白、呼吸和膜电位减少，活性氧增加，但成纤维细胞受影响较小。强力霉素使 A549 细胞增殖减慢 35%。细胞内 ATP 水平没有变化。强力霉素单独对细胞凋亡没有影响；然而，与治疗最后 2 天给予的吉西他滨联合使用时，强力霉素增加了 caspase 9 和 3/7 的活性，导致存活的 A549 细胞进一步减少 59%，成纤维细胞减少 24%，而单独使用吉西他滨则没有这种效果。A549 ρ°细胞不受强力霉素影响。在 A549 细胞中观察到的强力霉素的主要作用，如线粒体编码蛋白的减少和存活细胞的减少，也在癌细胞系 COLO357 和 HT29 中观察到。我们的结果表明，强力霉素通过吉西他滨抑制癌细胞增殖并诱导细胞凋亡。
