Abstract
Evasion of apoptosis is associated with treatment resistance and metastasis in colorectal cancer (CRC). Various cellular processes are associated with evasion of apoptosis. These include overexpression of pro-apoptotic proteins (including p53 and PD-L1), anti-apoptotic proteins (BIRC7/Livin and Bcl-2), chemokine receptors (including DARC), and dysregulation of DNA mismatch repair proteins (including MSH2 and PMS2). The aim of this study was to determine the effect of folinic acid, 5-FU and oxaliplatin (FOLFOX) as a single agent and aspirin plus FOLFOX in various combinations on the aforementioned proteins in human CRC, SW480 cell line and rat models of N-Methyl-N-Nitrosourea (NMU)-induced CRC. In addition, effects of the NMU-induced CRC and chemotherapeutic regimens on haematological and biochemical parameters in the rat models were studied. Immunohistochemistry, immunofluorescence and immunoblot techniques were used to study the expression pattern of the related proteins in the human CRC cells pre- and post-treatment. Double contrast barium enema, post-mortem examination and histological analyses were used to confirm tumour growth and the effect of the treatment in vivo in rat models. Notably, we found in human mucinous CRC, a significant increase in expression of the BIRC7/Livin post-FOLFOX treatment compared with pre-treatment (p = 0.0001). This increase provides new insights into the prognostic role of BIRC7/Livin in evasion of apoptosis and facilitation of treatment resistance, local recurrence and metastasis particularly among mucinous CRCs post-FOLFOX chemotherapy. These poor prognostic features in the CRC may be further compounded by the significant suppression of DARC, PD-L1, PMS2 and overexpression of MSH2 and anti-apoptotic Bcl-2 and p53 proteins observed in our study (p < 0.05). Importantly, we found a significant reduction in expression of BIRC7/Livin and reactivation of DARC and PD-L1 with a surge in Annexin V expression in rat models of CRC cells post-treatment with a sequential dose of aspirin plus FOLFOX compared with other treatments in vivo (p <0.05). The mechanistic rational of these effects underscores the importance of expanded concept of possible aspirin combination therapy with FOLFOX sequentially in future CRC management. Validation of our findings through randomized clinical trials of aspirin plus FOLFOX sequentially in patients with CRC is therefore warranted.
Highlights
Today, colorectal cancer (CRC) is a significant health problem with a non-uniform increase in incidence, treatment resistance and mortality across the globe [1, 2]
Targeting evasion of apoptosis with aspirin plus FOLFOX in colorectal cancer to significantly increased treatment efficacy and improved survival in CRC this treatment modality may be accompanied by complications such as myelotoxicity, neurotoxicity, non-alcoholic fatty liver disease and sinusoid obstruction syndrome [46]
Our study uncovers that mucinous CRC may serve as comfortable niche for inhibitor of apoptosis proteins such as baculoviral IAP repeat-containing protein-7 (BIRC7)/Livin to strive and facilitate treatment resistance, local recurrence and metastasis especially after neoadjuvant chemotherapy with FOLFOX
Summary
Colorectal cancer (CRC) is a significant health problem with a non-uniform increase in incidence, treatment resistance and mortality across the globe [1, 2]. In sub-Saharan Africa, where cancer registries may lack sufficient resources and there exists a paucity in cancer research, CRC disproportionately presents with advanced stage at diagnosis and a high mortality rate compared to the Western world [2, 3] These CRC disparities are due in part to issues that include grossly inadequate resources [4] and decreased prioritization of research that focuses on understanding the biology and clinicopathologic features of the disease. Four consensus molecular sub-types (CMS) of CRC have been documented, and they include: CMS1 (MSI Immune, 14%) characterized by hypermutation, microsatellite instability (MSI), and strong immune activation; CMS2 (Canonical, 37%) characterized by epithelial, chromosomally unstable features, and clear WNT and MYC signalling activation; CMS3 (Metabolic, 13%) characterized by metabolic dysregulation; and CMS4 (Mesenchymal, 23%) characterised by marked transforming growth factor β activation, stromal disruption and angiogenesis [8]. These classifications of CRC may convey important prognostic information for management of the disease
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