Rosmarinic acid as a targeted modulator of NF-κB signaling in colorectal cancer: A promising adjunct to chemotherapy

Abstract

We commend the work of Liu et al, who provide compelling preclinical evidence that rosmarinic acid (RA), a natural dietary polyphenol, exerts potent anti-tumor effects in colorectal cancer (CRC) by selectively suppressing the NF-κB signaling pathway. The study’s integrative approach—encompassing molecular docking, transcriptional analysis, and apoptosis induction—demonstrates RA’s ability to inhibit key oncogenic mediators, including cyclin D1 and MYC. Notably, RA enhances the efficacy of chemotherapeutics such as 5-fluorouracil and oxaliplatin synergistically, suggesting its potential as a chemosensitizer to overcome resistance. Given RA’s established safety profile and its broad spectrum of biological activities, this study provides a strong rationale for advancing RA toward translational applications in CRC management. We highlight the relevance of this work in the broader context of natural compound-based therapeutics and inflammation-driven tumor biology.

Key Words: Apoptosis; Combination chemotherapy; Drug resistance; Phytochemicals; Rosmarinic acid

Core Tip: This Letter to the Editor underscores the novel findings by Liu et al, revealing rosmarinic acid (RA)’s role in inhibiting colorectal cancer (CRC) progression via NF-κB signaling suppression and its potential as a natural, safe chemosensitizer against 5-fluorouracil and oxaliplatin resistance. We underscore the therapeutic relevance of these findings, emphasizing RA’s potential as a safe, natural chemosensitizer in CRC treatment and its promising role in overcoming chemoresistance through modulation of inflammation-driven tumor pathways.

TO THE EDITOR

We read with great interest the study by Liu et al[1] titled “Natural compound rosmarinic acid displays anti-tumor activity in colorectal cancer cells by suppressing nuclear factor-kappa B signaling”. The authors present compelling experimental evidence supporting the anti-cancer efficacy of rosmarinic acid (RA), a naturally occurring polyphenol, in colorectal cancer (CRC). This study integrates molecular docking, transcriptional profiling, luciferase reporter assays, and apoptosis evaluation to delineate RA’s mechanistic role in targeting NF-κB signaling in CRC cells.

A notable strength of this study lies in its systematic assessment across six CRC cell lines, ensuring the reproducibility and generalizability of the findings. The observed dose-dependent cytotoxicity of RA against HCT116, HT29, LoVo, RKO, SW480, and SW620 cells provides a solid foundation for future preclinical studies. Specifically, Liu et al[1] reported that RA exerted IC₅₀ values ranging between 100-200 μg/mL across CRC cell lines at 24 hours, confirming its potent cytotoxic activity. Furthermore, co-treatment with RA reduced the IC₅₀ of 5-fluorouracil (5-FU) and oxaliplatin by approximately 30%-50%, suggesting a chemosensitization effect. The authors report a significant reduction in cell viability and proliferation markers (cyclin D1, MYC, cyclin A1), along with robust induction of apoptosis as evidenced by caspase-3 cleavage and Bcl-2 suppression[1]. This multifaceted anti-tumor action highlights RA’s versatile pharmacological effects.

Particularly commendable is the detailed dissection of the NF-κB signaling pathway. Through in silico molecular docking, RA was shown to fit within the ATP-binding pocket of IKKβ, the catalytic subunit responsible for NF-κB activation. Specifically, RA formed hydrogen bonds with key residues such as Glu97 and Lys44 and hydrophobic interactions with Met96 within the ATP-binding cleft of IKKβ, achieving a binding energy of -8.2 kcal/mol, indicating a stable and favorable interaction. This was experimentally validated by decreased phosphorylation of NF-κB p65 and suppression of NF-κB-driven transcriptional activity, as demonstrated through luciferase assays and qRT-PCR. These results align with prior studies implicating NF-κB as a central player in CRC pathogenesis and therapy resistance[2,3]. Moreover, RA has been reported to inhibit STAT3 phosphorylation and suppress PI3K/AKT signaling, both of which are critical in CRC progression and chemoresistance, suggesting broader therapeutic potential beyond NF-κB inhibition[4]. Importantly, RA not only attenuated basal NF-κB activity but also inhibited lipopolysaccharide-induced activation[5], suggesting its potential to modulate both intrinsic and extrinsic inflammatory cues in the tumor microenvironment.

Another significant aspect of the study is the demonstration that RA sensitizes CRC cells to conventional chemotherapeutics. Both 5-FU and oxaliplatin, widely used in first-line CRC regimens, exhibited enhanced cytotoxicity in the presence of RA. This finding is particularly relevant given the high rates of acquired resistance to these agents in clinical settings. NF-κB has been previously implicated in chemoresistance by promoting cell survival, epithelial-to-mesenchymal transition (EMT), and DNA repair mechanisms[6,7]. By targeting this axis, RA may reverse or prevent resistance phenotypes, a therapeutic strategy increasingly recognized in cancer pharmacology. RA’s inhibition of NF-κB may suppress EMT markers and impair DNA damage repair mechanisms, both key contributors to chemoresistance in CRC. This aligns with emerging clinical trial data targeting NF-κB pathways to overcome resistance.

The translational implications of Liu et al’s[1] work are considerable. RA is widely recognized for its antioxidant, anti-inflammatory, and neuroprotective effects and is already used in food and cosmetic industries, which may facilitate its repositioning as an adjunct therapeutic in oncology[8]. Nevertheless, RA’s poor oral bioavailability remains a major limitation, attributed to rapid metabolism and limited intestinal absorption. Nanoparticle-based delivery systems and structural analog development are potential strategies under exploration to overcome these barriers[9]. However, further studies are needed to assess the pharmacokinetic properties, metabolic stability, and optimal dosing strategies of RA in vivo to facilitate its clinical translation. Moreover, rigorous clinical evaluation under stringent regulatory frameworks will be necessary to reposition RA as an oncological therapeutic, despite its GRAS status for food applications. Comprehensive preclinical animal studies and early-phase clinical trials will be essential to validate RA’s therapeutic efficacy, safety, and pharmacokinetic profile before clinical application.

Unlike synthetic inhibitors of NF-κB that may exert off-target effects or dose-limiting toxicities, RA’s safety profile and dietary origin offer a distinct advantage. Compared to other NF-κB inhibitors like curcumin and resveratrol, RA demonstrates comparable anti-inflammatory efficacy with superior stability under oxidative conditions. Unlike bortezomib, a proteasome inhibitor with systemic toxicities, RA’s natural origin may confer a more favorable safety margin for long-term adjunct therapy. Nonetheless, high concentrations of RA have been associated with oxidative stress induction and mitochondrial dysfunction in non-malignant cells[10], warranting dose-optimization studies to define a therapeutic window. Recent studies have shown that RA can also modulate the gut microbiota and intestinal barrier function, both of which are critical in CRC initiation and progression[11,12]. RA’s modulation of the gut microbiota may attenuate pro-inflammatory cytokine release and microbial-derived NF-κB activation, thereby synergistically enhancing its anti-tumor effects. Thus, the potential of RA as a dual-action agent—targeting tumor cells and improving gut homeostasis—warrants further investigation. However, notable limitations include the absence of in vivo validation to confirm efficacy and bioavailability concerns inherent to polyphenolic compounds like RA. Additionally, while the study emphasizes NF-κB suppression, alternative mechanisms (e.g., modulation of oxidative stress pathways) could also contribute to the observed anti-tumor effects. Further studies are necessary to verify these findings under physiological conditions.

In the context of traditional Chinese medicine (TCM), where RA is a key bioactive component in several medicinal herbs, this study aligns with a broader movement to integrate TCM-derived compounds into modern oncology[13]. Such efforts are essential to diversify our therapeutic armamentarium and address the limitations of current standard-of-care approaches.

Potential predictive biomarkers for the efficacy of RA may include elevated basal NF-κB p65 phosphorylation, cyclin D1 overexpression, and gut microbiota dysbiosis, particularly an altered Firmicutes/Bacteroidetes ratio. Although there are currently no registered clinical trials evaluating RA in CRC, pilot phase I studies focusing on safety, pharmacokinetics, and combination strategies with 5-FU in chemoresistant CRC could provide valuable insights. To enhance therapeutic precision, future investigations should prioritize patient cohorts with NF-κB-driven CRC, such as those with KRAS mutations or microsatellite-stable tumors. Biomarker profiling, particularly assessing p65 phosphorylation status, could further optimize patient selection. Given that RA can be readily extracted from abundant herbal sources or synthesized chemically, scalable production and global accessibility are feasible, supporting its potential for widespread clinical application. Moving forward, research efforts should emphasize pharmacokinetic characterization, development of nanoparticle-based RA formulations, evaluation in orthotopic CRC mouse models, and the integration of biomarker-guided approaches into clinical trial designs.

Conclusion

In conclusion, Liu et al provide a thorough and insightful exploration of RA’s anti-cancer mechanisms in CRC, particularly through NF-κB inhibition. Future work may extend these findings to in vivo models, explore pharmacokinetics and bioavailability, and evaluate RA’s efficacy in chemotherapy-resistant CRC subtypes or in inflammation-driven CRC models. This study adds contributes meaningfully to the growing body of evidence supporting natural product-based therapeutics and reinforces the central role of inflammatory signaling in tumor biology.