The effect of animal venom in the treatment of pancreatic and colorectal cancer
Knight, E. 2021. The effect of animal venom in the treatment of pancreatic and colorectal cancer. PhD Thesis Canterbury Christ Church University School of Human and Life Sciences
|Qualification name||Doctor of Philosophy|
Pancreatic and colorectal cancer are aggressive, difficult to target cancers with new therapeutic options desperately required to improve prognosis. Animal venoms are useful in drug discovery due to huge variety of bioactive components evolved over millions of years. Venom has already been utilised in drug discovery with several venom derived drugs currently on the market.
A plate-based resazurin assay was used to determine cytotoxicity of a panel of cobra venoms against BxPC-3 pancreatic and SW620 colorectal cancer cell lines in-vitro. African spitting cobra (Afronaja) venoms displayed selective toxicity against SW620 cells compared to non-spitting and Asian cobra venoms. Five Afronaja venoms were fractionated using HPLC then the venom components were rescreened in a miniaturised resazurin assay. Dose response curves for both lines were performed using selected fractions, giving IC50 values between 17-225 μg/ml.
Four venom fractions were analysed using Mass Spectrometry (MS) and identified as cytotoxins. MS outputs plus bioinformatic techniques predicted likely sequences for each fraction. A structure activity relationship was performed and AA residue 7 and AAs 26-29 were identified as conferring the most significant selective toxicity.
Finally, a preliminarily qPCR study assessed the effect of each fraction on the tested cell lines. This study investigated 20 genes commonly mis-regulated in pancreatic and colorectal cancer. The cell lines were exposed to three venom fractions and regulation of each gene assessed compared to untreated controls. SMAD4, Tp53, WNT1 and EGFR genes were significantly upregulated following addition of venom and MMP9 and Bcl-2 were significantly downregulated in this preliminary study. A larger scale qPCR study should be performed to confirm these findings and assess other potential genetic alterations caused by the venom fraction to assess the potential for development into an anti-cancer treatment option.
|Keywords||Animal venom; Pancreatic cancer; Colorectal cancer; Treatment; Effect|
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|Deposited||04 Apr 2022|
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