alloin and Colorectal-Neoplasms

CPT-11 is one of the drugs employed in colorectal cancer treatment and has faced challenges in the form of resistance. The insulin-like growth factor 1 receptor is a tyrosine kinase receptor that mediates cancer cell survival and drug resistance. It is frequently overexpressed in colorectal cancer and has previously been identified as a microRNA target. MicroRNAs are non-coding RNA molecules that regulate gene function by suppressing messenger RNA translation. Studies have demonstrated that natural compounds can regulate microRNA function and their target genes. Therefore, combining natural compounds with existing cancer drugs can enhance the therapeutic efficacy. We investigated a natural compound, Aloin, for the potential sensitization of colorectal cancer to CPT-11. We used western blot, MTT cell viability assay, flow cytometry, and microRNA/gene knockdown and overexpression experiments, as well as an in vivo mouse model. Our investigation revealed that combining Aloin with CPT-11 exerts an enhanced anti-tumor effect in colorectal cancer. This combination reduced cell viability and induced apoptosis, both in vivo and in vitro. Furthermore, this combination upregulated miRNA-133b, while downregulating the IGF1R and its downstream MEK/ERK, and PI3K/AKT/mTOR pathways. Our findings suggests that CPT-11 and Aloin are potential combination treatment partners against colorectal cancer. MicroRNA-133b may serve as a co-therapeutic target with IGF1R against colorectal cancer, which might overcome the existing treatment limitations.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Irinotecan; MAP Kinase Signaling System; Mice; MicroRNAs; Mitogen-Activated Protein Kinase Kinases; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

Aloe vera (L.) Burm.f. is widely used as laxative drugs, cosmetics, and functional food due to a variety of therapeutic effects. However, several studies indicated a colonic carcinogenic activity of Aloe vera. But the underline mechanism has not been well clarified. This study aimed to explore the potential mechanism at the post-transcriptional level. Identification of Differential Expressed Alternative Splicing (DEAS) genes and events and the corresponding functional enrichment analyses were conducted on RKO cells after treated with Aloe vera aqueous extract and its two active components, aloin and aloesin. And RT-qPCR was conducted for validation. Results indicated that they induced 2200, 2342 and 2133 DEAS events, respectively. The GO enrichment and the COG classification results of DEAS genes showed that they were associated with transcription, as well as functions like signal transduction mechanisms. Moreover, DEAS genes related to the two colorectal cancerous pathways, Wnt and Notch pathways, were annotated. In conclusion, aloe extract, aloin and aloesin significantly regulated the DEAS profile of RKO cells. The colonic carcinogenicity of Aloe vera may due to its post-transcriptional regulatory activity through Alternative Splicing (AS) on genes, especially on Wnt-related and Notch-related key genes.

Topics: Aloe; Alternative Splicing; beta Catenin; Carcinogenesis; Cell Line, Tumor; Chromones; Colorectal Neoplasms; Emodin; Glucosides; Humans; Plant Extracts; Receptors, Notch; RNA Processing, Post-Transcriptional; Signal Transduction; Wnt Proteins

Aloe vera (L.) Burm. f. (Aloe vera) is a common Traditional Chinese Medicine (TCM) recorded in Pharmacopoeia of the People's Republic of China (version 2015). It has been traditionally used for treatment of constipation. Aloe vera requires much attention for its safety evaluation because several studies have reported the association between oral consumption of Aloe vera and the development of colorectal cancer (CRC). However the material basis and molecular mechanism are.still less well elucidated. Although Wnt/β-catenin and Notch signaling pathway have been known to be closely related to the initiation and development of CRC, the impacts of Aloe vera on these cancerous pathways have not been completely determined yet.. Hence, this study aimed to study the impacts of Aloe vera on the Wnt/β-catenin and Notch signaling pathway, as well as proliferation of CRC cells.. Firstly, the effects of Aloe vera aqueous extract and its two active components (aloin and aloesin) on the Wnt/β-catenin and Notch signaling pathway were studied by luciferase reporter, RT-qPCR, western blotting and immunofluorescence assays, respectively. Furthermore, RNA sequencing analysis (RNA-seq) was then performed to verify their regulatory activities on the Wnt-related and Notch-related genes expression. Finally, their impacts on RKO cell proliferation and cell cycle phase were also evaluated via MTT assay and cell cycle analysis.. Our results indicate that the aqueous extract of Aloe vera and its active component aloin activated the Wnt/β-catenin pathway and inhibited the Notch signaling pathway only in the presence of Wnt3a. While aloesin was characterized to directly activate the Wnt/β-catenin pathway and inhibit the Notch pathway independent of Wnt3a. Within 24h, the Aloe vera extract and its two components were failed to affect the proliferation or cell cycle phase of RKO cells. Nevertheless, in the presence of Wnt3a, the aqueous extract of Aloe vera with the concentration of 33.3 μg/ml start to promote the cell proliferation of RKO cells after 48h incubation.. In conclusion, this study showed that Aloe vera extract and its active component aloin activated the Wnt/β-catenin pathway and inhibited the Notch pathway in the presence of Wnt3a. While another active component, aloesin, activated the Wnt/β-catenin pathway and inhibited the Notch signaling pathway independent of Wnt3a. Given that Wnt/β-catenin and Notch pathway are closely associated with the progression of CRC, these findings would be helpful to better understand the colonic carcinogenicity of Aloe vera.

Topics: Aloe; Animals; beta Catenin; Cell Line; Cell Proliferation; Chromones; Colorectal Neoplasms; Emodin; Glucosides; Humans; Mice; Plant Extracts; Receptors, Notch; Signal Transduction; Wnt Proteins

In a model of dimethylhydrazine-induced colorectal tumors in male mice aloin- or sennoside-enriched diets (0.03%) did not promote incidence and growth of adenomas and carcinomas after 20 weeks. Furthermore, in anthranoid-fed mice no significant changes in serum electrolytes as well as parameters of hepato- and nephrotoxicity were observed.

Topics: 1,2-Dimethylhydrazine; Adenoma; Aloe; Animals; Anthraquinones; Carcinogens; Carcinoma; Cathartics; Colorectal Neoplasms; Dimethylhydrazines; Emodin; Incidence; Male; Mice; Plants, Medicinal; Random Allocation; Senna Extract; Sennosides