Abstract
Colorectal cancer is primarily a disease of the developed world. The incidence rate has continued to increase over time, reflecting both demographic and lifestyle changes, which have resulted in genomic and epigenomic modifications. Many of the epigenetic modifications occur in genes known to be closely associated with embryonic development and cellular growth. In particular, the paired box (PAX) transcription factors are crucial for correct tissue development during embryogenesis due to their role in regulating genes involved in proliferation and cellular maintenance. In a number of cancers, including colorectal cancer, the PAX transcription factors are aberrantly expressed, driving proliferation and thus increased tumour growth. Here we have synthesized and used a small molecule PAX inhibitor, EG1, to inhibit PAX transcription factors in HCT116 colorectal cell cultures which resulted in reduced proliferation after three days of treatment. These results highlight PAX transcription factors as playing an important role in the proliferation of HCT116 colorectal cancer cells, suggesting there may be a potential therapeutic role for inhibition of PAX in limiting cancer cell growth.
Highlights
The incidence of colorectal cancer (CRC) in individuals aged 20 to 49 years has continued to escalate throughout Australasia, Europe and Northern America over the last decade [1]
We show here that EG1 treatment was able to successfully slow HCT116 colorectal carcinoma cell proliferation, and we present evidence that this occurs by targeting paired box (PAX) proteins involved in regulating cell proliferation
To attach the final aromatic ring needed for EG1, 2-methoxybenzoic acid [5] was converted into acid chloride 6 which was immediately reacted with the amine acetate 4 to yield the EG1 methyl ester 7 (Figures 1, 2)
Summary
The incidence of colorectal cancer (CRC) in individuals aged 20 to 49 years has continued to escalate throughout Australasia, Europe and Northern America over the last decade [1]. It is thought that the ongoing rise in incidence rates may be due to newly evolving lifestyles which correlate with genetic and epigenetic changes [2]. CRC originates from polyps forming on the mucous membrane of the large intestines which are predisposed to become malignant over time [5]. The polyps can progress into these malignant carcinomas due to the expressional change of genes involved in cell cycling, leading to increased cellular division and proliferation, as well as evasion of cell death [5]
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