Effect of Diacerein on HOTAIR/IL-6/STAT3, Wnt/β-Catenin and TLR-4/NF-κB/TNF-α axes in colon carcinogenesis
Introduction
Colorectal cancer (CRC) is a common worldwide malignancy with about two-thirds of all diagnosed cases occurring in the more developed regions of the world. CRC originates in the epithelial cell lining of the colon or rectum. It is associated with a series of histopathological and molecular alterations that ultimately transform the normal colonic epithelium into an invasive carcinoma (Khan et al., 2018). Globally, CRC is the second most commonly diagnosed cancer in females and the third in males with 1.8 million newly diagnosed cases and almost 861,000 deaths annually (Su et al., 2019). Indeed, CRC represents the third most common cause of cancer-related mortality in both genders worldwide (Pervaiz et al., 2021).
The etiology of CRC is multifactorial, involving the interaction between various exogenous chemical and endogenous biological factors such as the individual’s diet, the genetic predisposition, the age, the extent of physical activity and smoking (Al-Ghafari et al., 2019). Interestingly, epidemiological studies have reported that the consumption of toxicants through diets rich in saturated fat plays a central role in the individual’s susceptibility to CRC, contributing to up to 80% of documented CRC cases (Harris et al., 2016). The current therapeutic strategies for CRC include surgery, chemotherapy and radiotherapy. Of note, surgery is suitable only at early stages of disease. For advanced stages, chemotherapy and radiotherapy are applied; however their use is accompanied by deleterious side effects, such as chemotherapy-induced organ toxicity (Kumar and Agnihotri, 2019). Therefore, it is imperative to search for alternative safe and effective anti-tumourigenic agents to combat CRC progression.
Diacerein (DIA) is an anti-inflammatory drug clinically prescribed for the treatment of osteoarthritis (El-Sherbiny et al., 2021). It is an anthraquinone derivative that shows non-steroidal pro-inflammatory cytokine inhibitor activity (Steinecker-Frohnwieser et al., 2014). The tumour environment is rich in pro-inflammatory cytokines which in turn promotes several oncogenic signalling pathways. Among these cytokines, Interleukin-6 (IL-6), which has received particular attention in the pathogenesis of various types of cancer via triggering downstream STAT3 signalling pathway (Xie et al., 2019), (Wang et al., 2018).
In this context, DIA has been reported to instigate apoptosis of breast cancer cells via inhibition of IL-6/STAT3 ( Bharti et al., 2016a). Therefore, targeting IL6/STAT3 axis could be a potential blueprint for cancer therapy. A recent study has demonstrated the anti-neoplastic efficacy of DIA in CRC through targeting IL-6/K-Ras/Notch/NF-κB p65, p-Akt/GSK3-β/β-catenin/cyclinD-1, and Nur77 (Abdel-Latif et al., 2022).
This report will investigate IL-6/STAT-3/HOTAIR lncRNA as an additional potential molecular target for DIA using 1,2-dimethylhydrazine-induced CRC model. Moreover, the involvement of TLR4/NF-κB/ TNF-α and Wnt/β-Catenin axes in anti-proliferative efficacy of DIA will also be investigated.
Section snippets
Drugs and chemicals
1,2-dimethylhydrazine (DMH) was purchased from Sigma–Aldrich (#D161802, Sigma–Aldrich, St. Louis, MO, USA). DMH was freshly dissolved in 1 mM EDTA and the pH was adjusted to 6.5 using NaOH to maintain stability of the carcinogen. Diacerein (DIA) was purchased from Eva Pharma Company (Cairo, Egypt). All other chemicals were of the highest purity and the highest analytical grade.
Animals and experimental design
Adult male Albino Wistar rats (200–250 g) were purchased from the breeding unit of Holding Company for Biological
DIA treatment ameliorates CRC progression in vivo and induces cell cytotoxicity in vitro
Histopathological examination of normal colon tissues confirmed the regular arrangement of surface and crypt epithelial cells with no signs of dysplasia, adenoma or carcinoma (Fig. 2 A). Similar structural features have been shown upon microscopic examination of the DIA control group (Fig. 2 A). DMH injection drove a significant structural alteration in the colon tissue as evidenced by the appearance of colonic adenomas with cystic dilation, as well as intestinal adenomas with focal invasion of
Discussion
The present study presents IL-6/STAT3/HOTAIR, TLR4/NF-κB/TNF-α and Wnt/β-Catenin as potential molecular targets for DIA-induced anti-proliferative effect in experimentally induced CRC. DIA administration blocked these axes with subsequent apoptotic, anti-inflammatory, and anti-angiogenic effects. DIA is an FDA approved drug with well-defined pharmacokinetics, pharmacodynamics, along with good metabolic and safety profiles. Hence, the present study suggests DIA’a repurposing in CRC management,
Funding
The work was supported by the Researchers Supporting programme (MA-006), AlMaarefa University, Riyadh, Saudi Arabia. The work was supported by Princess Nourah Bint Abdulrahman University Researchers Supporting Project number (PNURSP2022R171), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
CRediT authorship contribution statement
Nada H. Eisa, Nehal M. Elsherbiny, Mohamed El-Sherbiny: Conceptualization. Nada H. Eisa, Eman Said, Ahmed E. Khodir, Hasnaa Ali Ebrahim, Dalia Mahmoud Abdelmonem Elsherbini, Nehal M. Elsherbiny, Mohamed El-Sherbiny: Formal analysis. Dina Sabry, Mohamed El-Sherbiny: Methodology. Nada H. Eisa, Nehal M Elsherbiny, Mohamed El-Sherbiny: Project administration. Nada H. Eisa, Eman Said, Ahmed E Khodir, Dina Sabry, Hasnaa Ali Ebrahim,; Dalia Mahmoud Abdelmonem Elsherbini, Reem Altemani, Dania Mohammed
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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