AbstractDespite the considerable progress in cancer research which has been translated into better cancer care and decreased overall mortality rates in the last decade for numerous cancers, colorectal carcinoma (CRC) and leukaemia remain still one of the commonest malignancies worldwide. The compounds with improved anti-cancer activity that circumvent limitations of conventional chemotherapeutic agents are urgently searched. Artesunate (ART) and dihydroartemisinin (DHA) are the most active compounds of all semisynthetic derivatives of artemisinin (a natural extract of the Chinase plant, Artemisia annua L.) that have been proven to exert potent anti-cancer activity in vitro, in vivo and under human clinical trials.
ART and DHA contain a labile ring system, an endoperoxide bridge, which reductive cleavage by iron is a necessary prerequisite in their cytotoxicity. With ample evidence showing that the cytotoxicity of ART and DHA against cancer cells is linked with targeting a number of cellular proteins promoting tumorigenesis, the aim of this study was to provide additional molecular basis of ART and DHA activities in CRC HT-29-AK and leukaemia HL-60 cells in vitro.
Since the interior of most solid tumours are hypoxic (~1% O2), which has implications for cancer metastasis and resistance to anti-cancer agents clinically, the anti-cancer effects of ART and DHA were performed under laboratory standard normoxic condition (20% O2) and low oxygen tension (1% O2), which mimics the tumour microenvironment. With reported ability of aspirin (acetylsalicylic acid; ASA) to enhance the cytotoxicity of other anti-cancer agents, we postulated that ASA would equally enhance the cytotoxic effects of ART and DHA. The mechanistic basis of this interaction was evaluated in cultured HT-29-AK and HL-60 cells in normoxia (20% O2) and hypoxia (1% O2).
This study shows that ART and DHA treatment of HT-29-AK and HL-60 cells in normoxia effectively inhibited the growth of both cell lines and this inhibition was affected by oxygen availability. Upon combination, ART and DHA with ASA could reverse decreased susceptibility of HT-29-AK cells under hypoxic conditions to ART and DHA alone.
In conclusion, these data illustrate the importance of modeling the tumour microenvironment when developing novel therapeutic drug applications. We also show that ART and DHA co-treated with ASA might be effective combination regimen to enhance efficacy of chemotherapy in cancer cells. Given the broad spectrum of mediators involved in ART and DHA anti-cancer effects (alone and in combination with ASA), further studies are required to validate our observations and translate them into significance for cancer therapy.
|Date of Award||2016|
|Supervisor||Christopher Mee (Supervisor), Omar Janneh (Supervisor), Afthab Hussain (Supervisor) & Martin Cox (Supervisor)|