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Revisiting Luteolin Against the Mediators of Human Metastatic Colorectal Carcinoma: A Biomolecular Approach
Ankita Chakraborty1, Advaitha Midde2, Pritha Chakraborty1
1Integrative Biochemistry and Immunology Laboratory, Department of Animal Science, Kazi Nazrul University, Asansol, West Bengal, India.
Abstract:
Metastatic colorectal carcinoma (mCRC) is one of the prevalent subtypes of human cancers and is caused by the alterations of various lifestyle and diet-associated factors. β-catenin, GSK-3β, PI3K-α, AKT1, and NF-κB p50 are known to be the critical regulators of tumorigenesis and immunopathogenesis of mCRC. Unfortunately, current drugs have limited efficacy, side effects and can lead to chemoresistance. Therefore, searching for a nontoxic, efficacious anti-mCRC agent is crucial and of utmost interest. The present study demonstrates the identification of a productive and nontoxic anti-mCRC agent through a five-targets (β-catenin, GSK-3β, PI3K-α, AKT1, and p50)-based and three-tier (binding affinity, pharmacokinetics, and pharmacophore) screening strategy involving a series of 30 phytocompounds having a background of anti-inflammatory/anti-mCRC efficacy alongside 5-fluorouracil (FU), a reference drug. Luteolin (a phyto-flavonoid) was eventually rendered as the most potent and safe phytocompound. This inference was verified through three rounds of validation. Firstly, luteolin was found to be effective against the different mCRC cell lines (HCT-15, HCT-116, DLD-1, and HT-29) without hampering the viability of non-tumorigenic ones (RWPE-1). Secondly, luteolin was found to curtail the clonogenicity of CRC cells, and finally, it also disrupted the formation of colospheroids, a characteristic of metastasis. While studying the mechanistic insights, luteolin was found to inhibit β-catenin activity (a key regulator of mCRC) through direct physical interactions, promoting its degradation by activating GSK3-β and ceasing its activation by inactivating AKT1 and PI3K-α. Luteolin also inhibited p50 activity, which could be useful in mitigating mCRC-associated proinflammatory milieu. In conclusion, our study provides evidence on the efficacy of luteolin against the critical key regulators of immunopathogenesis of mCRC and recommends further studies in animal models to determine the effectiveness efficacy of this natural compound for treating mCRC in the future.
Insights
Luteolin, a natural phytocompound, shows potent efficacy against metastatic colorectal carcinoma (mCRC) by targeting key regulators like β-catenin and p50. This non-toxic agent effectively inhibits cancer cell growth and metastasis, offering a promising alternative for mCRC treatment.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Metastatic colorectal carcinoma (mCRC) is a prevalent cancer with limited treatment options.
- Key regulators like β-catenin, GSK-3β, PI3K-α, AKT1, and NF-κB p50 are crucial in mCRC development.
- Existing therapies for mCRC face challenges of efficacy, side effects, and chemoresistance.
Purpose of the Study:
- To identify a novel, non-toxic, and effective agent against mCRC.
- To screen phytocompounds targeting critical regulators of mCRC tumorigenesis and immunopathogenesis.
- To evaluate the anti-mCRC potential of luteolin.
Main Methods:
- A three-tier screening strategy (binding affinity, pharmacokinetics, pharmacophore) was employed.
- Thirty phytocompounds with known anti-inflammatory/anti-mCRC efficacy were screened against five key targets.
- Luteolin's efficacy was validated through in vitro assays against mCRC cell lines and mechanistic studies.
Main Results:
- Luteolin was identified as the most potent and safe phytocompound among the screened series.
- Luteolin demonstrated significant efficacy against various mCRC cell lines without affecting non-tumorigenic cells.
- Luteolin inhibited cancer cell clonogenicity, disrupted colospheroid formation, and modulated key signaling pathways (β-catenin, GSK3-β, AKT1, PI3K-α, p50).
Conclusions:
- Luteolin exhibits significant anti-mCRC activity by directly inhibiting key regulatory pathways.
- The compound's ability to target multiple crucial regulators makes it a promising candidate for mCRC therapy.
- Further in vivo studies are recommended to establish luteolin's therapeutic potential for mCRC.
