Abstract
BackgroundColorectal cancer is the third most-common cancer and the second most-common cause of cancer related death in UK. Although chemotherapy plays significant role in the treatment of colorectal cancer, morbidity and mortality due to drug resistance and cancer metastasis are yet to be eliminated. Recently, doxycycline has been reported to have cytotoxic and anti-proliferating properties in various cancer cells. In this study, whether doxycycline was apoptosis threshold lowering agent in colorectal cancer cells by targeting mitochondria was answered.ResultsThis study showed dose-dependent cytotoxic effects of cisplatin, oxaliplatin and doxycycline in HT29 colorectal cancer cells. Doxycycline showed inhibition of cytochrome-c-oxidase activity in these cells over a time-period. The pre-treatment of doxycycline reported statistically significant increased cytotoxicity of cisplatin and oxaliplatin compared to cisplatin and oxaliplatin alone. The caspase studies revealed significantly less expression and activity of caspase 3 in HT29 cells pre-treated with doxycycline compared to the cells treated with cisplatin and oxaliplatin alone.ConclusionsIt was concluded that doxycycline lowered the apoptotic threshold in HT 29 cells by targeting mitochondria. This also raised possible caspase-independent mechanisms of apoptosis in HT29 cells when pre-treated with doxycycline however this needs further research work.
Highlights
Colorectal cancer is the third most-common cancer and the second most-common cause of cancer related death in UK
Cytotoxicity of Drugs The cytotoxicity studies revealed dose dependent cytotoxic effects of cisplatin, oxaliplatin and doxycycline on HT 29 cells; the effect of doxycycline was much lower compared to the platinum compounds
Following the results of this experiment, cytotoxicity and cell proliferation studies were performed after 3 days of doxycycline treatment and they revealed statistically significant increased cytotoxicity and anti-prolifetative effects in HT29 cells after 3 days of doxycycline treatment compared to 24 hours of treatment (Figure 4)
Summary
Doxycycline has been reported to have cytotoxic and anti-proliferating properties in various cancer cells. Whether doxycycline was apoptosis threshold lowering agent in colorectal cancer cells by targeting mitochondria was answered. Tetracyclines (TCNs) have long been used widely in clinical practice as antibiotics in various bacterial, mycoplasma, chlamydiae, rickettsiae and protozoan infections. Their main mechanism of action involves inhibition of protein synthesis by restricting binding of aminoacyl t-RNA to 30 S ribosomes. A renewed interest in study of TCNs has evolved due to their ability to inhibit matrix metalloproteinases (MMPs) in various cancers such as prostate[2], melanoma[3], osteosarcoma[4], breast[5], leukaemia [6] and colorectal cancers[7].
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