Rosmarinic acid as a chemosensitizer in colorectal cancer: Targeting nuclear factor-kappa B pathway to overcome chemoresistance

Abstract

Colorectal cancer (CRC) is the third most common malignancy. However, the efficacy of current treatment strategies remains limited. In recent years, monomeric compounds from traditional Chinese medicine have received extensive attention in cancer therapy. Rosmarinic acid (RA), a natural phenolic acid, has multiple biological activities and exhibits anti-oncogenic effects in several cancers. Liu et al previously uncovered that RA could serve as a dual-action therapeutic agent in CRC. By suppressing nuclear factor-kappa B signaling via direct inhibition of inhibitory kappa B kinase beta, RA not only impedes tumor progression but also synergizes with first-line chemotherapeutics (5-fluorouracil/oxaliplatin) to reverse drug resistance. The authors demonstrate RA’s capacity to downregulate nuclear factor-kappa B-driven oncogenes and enhance chemotherapeutic cytotoxicity in vitro through integrative approaches, including molecular docking, luciferase assays, and functional validation. While these findings position RA as a cost-effective adjuvant in precision oncology, critical clinical translational gaps remain, including optimizing RA’s in vivo bioavailability, validating systemic safety in combinatorial regimens, and elucidating its immunomodulatory effects within the tumor microenvironment. This underscores the urgency of bridging phytochemistry and clinical oncology, advocating for biomarker-driven animal studies and phase I trials to translate RA’s potential into actionable CRC therapies. By addressing these hurdles, RA could emerge as a paradigm-shifting agent, harmonizing natural product efficacy with modern therapeutic precision.

Key Words: Rosmarinic acid; Colorectal cancer; Nuclear factor-kappa B signaling; Chemoresistance; Chemosensitizer; Natural products

Core Tip: This study demonstrates that rosmarinic acid (RA), a natural polyphenol, suppresses colorectal cancer progression by inhibiting nuclear factor-kappa B signaling and synergizes with chemotherapeutics (5-fluorouracil/oxaliplatin) to overcome drug resistance. RA’s dual role as a cytotoxic agent and chemosensitizer highlights its potential in precision oncology. While in vitro findings are promising, future research must address RA’s bioavailability, in vivo efficacy, and clinical safety to translate this natural compound into actionable colorectal cancer therapies.

INTRODUCTION

Colorectal cancer (CRC) ranks as the third most prevalent malignancy worldwide. Its incidence and mortality rates are on the rise, particularly in patients with advanced disease[1,2]. Chemoresistance is the primary cause of treatment failure[3,4]. While surgery, radiotherapy, and targeted therapies have progressed over the years, the five-year survival rate for metastatic CRC remains under 15%[5]. Traditional chemotherapeutic drugs like 5-fluorouracil (5-FU) and oxaliplatin (OXA) are commonly used as first-line treatments[6]. Nevertheless, the development of chemoresistance highlights the urgent need to develop new sensitization strategies.

In recent years, natural compounds have become highly valued for their multi-target properties, low toxicity, and wide availability[7,8]. Rosmarinic acid (RA) is a phenolic compound derived from natural plants. RA has a variety of biological activities, such as antioxidant, anti-inflammatory, and antimicrobial effects[9]. Numerous studies have shown that RA has significant anticancer activity in various cancers, including lung, liver, and stomach cancer[9,10]. RA can modulate key biological processes, including cell proliferation, apoptosis, invasion, and metastasis, to inhibit tumor development[11,12]. Nonetheless, the specific mechanisms of RA in CRC cells and its synergistic effects with chemotherapeutic drugs are still poorly understood.

To that end, Liu et al[13] conducted a study that combined molecular docking, functional experiments, and mechanistic validation. They uncovered that RA targets inhibitory kappa B kinase beta to inhibit the nuclear factor-kappa B (NF-κB) signaling pathway. Furthermore, RA could enhance the cytotoxicity of 5-FU/OXA, providing a new perspective for using natural compounds in CRC chemotherapy.

RA AS A CHEMOSENSITIZER IN CRC

Chemotherapy sensitization has emerged as a promising strategy to overcome drug resistance. RA is a polyphenol naturally found in herbs such as rosemary, basil, and mint. It has garnered attention for its potential as a chemosensitizer for CRC. In a previous study by Liu et al[13] systematically unveiled the triple antitumor mechanisms of RA in CRC treatment. First, RA exhibited dose-dependent cytotoxicity against six cell lines, inducing apoptosis by downregulating cyclin D1 and MYC expression. Second, molecular docking confirmed that RA specifically binds to the adenosine triphosphate pocket of inhibitory kappa B kinase beta, significantly reducing NF-κB luciferase activity and the phosphorylation level of the p65 subunit. Moreover, RA also abolished lipopolysaccharide-induced overactivation of NF-κB, blocking pro-cancer signaling at the transcriptional level. In addition, when combined with first-line chemotherapeutic drugs 5-FU and OXA, RA reversed chemoresistance by inhibiting the NF-κB pathway, significantly enhancing drug toxicity, and providing experimental evidence for clinical combination therapy.

This finding is further corroborated by previous studies[14,15]. Jin et al[14] previously demonstrated that RA could inhibit Toll-like receptor 4-mediated co-activation of NF-κB/signal transducer and activator of transcription 3, downregulate anti-apoptotic factors such as B-cell lymphoma-2 and survivin, and reshape the inflammatory microenvironment to suppress tumorigenesis in a colitis-associated cancer mouse model. Meanwhile, Liu et al[15] revealed that RA targets the cyclooxygenase-2/myosin X axis and synergizes with ginsenoside ginsenoside Rg1 to block programmed cell death protein 1/programmed death-ligand 1 signaling, inhibiting CRC metastasis. Notably, NF-κB, as a central regulatory hub, directly activates cyclooxygenase-2 transcription and promotes the production of prostaglandin E2, which in turn enhances NF-κB activity, forming a pro-oncogenic positive feedback loop. The aberrant activation of the NF-κB pathway is a core driver of CRC progression and chemoresistance[16]. RA’s inhibition of NF-κB may indirectly weaken the cyclooxygenase-2/prostaglandin E2 axis, thereby inhibiting proliferation and synergistically blocking invasion and metastasis, indicating RA’s unique advantage of multi-point intervention.

RA: FUTURE PERSPECTIVES

As a naturally derived food additive, RA has obtained multiple international food safety certifications, including those from the European Food Safety Authority and the United States Food and Drug Administration. The safety data accumulated from its long-term use provides a unique advantage for clinical translation[17]. In contrast to synthetic chemosensitizers (such as the cyclooxygenase-2 inhibitor, celecoxib), the natural origin of RA significantly reduces the risk of hepatorenal toxicity and may circumvent drug resistance caused by long-term use. Nonetheless, RA’s low water solubility and significant first-pass effect severely limit its clinical application potential[17]. Therefore, it is imperative to develop solutions based on advanced drug delivery systems. For instance, liposomal encapsulation technology can enhance the intestinal absorption of RA through the phospholipid bilayer, and folate receptor-targeted polymeric nanoparticles can achieve tumor-specific accumulation by exploiting the high expression of folate receptors in CRC cells. Despite advancements in liposomal and polymeric nano-delivery systems, key limitations remain unresolved, including scalability, stability, and off-target toxicity. For instance, although folate-targeted nanoparticles improve drug accumulation in tumors, their efficacy is compromised by protein corona formation in the systemic circulation. Therefore, future efforts must prioritize hybrid delivery platforms and artificial intelligence-driven design to overcome these challenges.

Although in vitro experiments have shown that the combination of RA and 5-FU can significantly increase the apoptosis rate of cancer cells, the spatiotemporal heterogeneity of its in vivo efficacy still warrants further validation through patient-derived xenograft models. Specifically, liquid chromatography-tandem mass spectrometry technology could offer a means to dynamically monitor the pharmacokinetic characteristics of RA and its metabolites (such as RA glucuronide) in tumor tissues. At the same time, combining multiplex immunofluorescence to analyze the remodeling effects on the tumor microenvironment, including the infiltration degree of CD8+ T cells, the ratio of M1/M2 macrophages, and the regulatory effects of immune inhibitory factors such as interleukin-10/transforming growth factor β could offer more critical mechanistic insights.

Regarding clinical translation strategies, a phased approach is recommended. Phase I clinical trials could employ a 3 + 3 dose-escalation design to evaluate the maximum tolerated dose and dose-limiting toxicities of RA monotherapy (intravenous liposomal formulation) or in combination with the FOLFOX regimen, with a particular focus on potential cardiotoxicities such as QT interval prolongation. Phase II trials could incorporate the analysis of circulating biomarkers, for instance, by using the Luminex multiplex detection platform to track the dynamic changes of downstream factors in the NF-κB pathway (such as interleukin-6 and tumor necrosis factor alpha) and assessing therapeutic heterogeneity in conjunction with the mutation abundance of Kirsten rat sarcoma viral oncogene homologue/neuroblastoma RAS in circulating tumor DNA.

Moreover, leveraging artificial intelligence-driven drug discovery platforms, such as using AlphaFold2 to predict target binding conformations and employing generative adversarial networks to generate novel RA derivatives, holds promise for overcoming the structural optimization bottleneck of natural products. To achieve this goal, there is an urgent need to establish a multidisciplinary research consortium, with pharmacists focusing on the development of nanodelivery systems, clinical oncologists designing biomarker-based adaptive clinical trials, and bioinformaticians constructing multi-omics predictive models to detect chemoresistance in CRC patients. By adopting a “nature-synthetic” synergistic strategy, the potential of natural compounds in precision oncology can be fully realized.

CONCLUSION

The dual role of RA in targeting inhibitory kappa B kinase beta to inhibit the NF-κB pathway and enhancing the efficacy of chemotherapy provides a theoretical basis for the application of natural compounds in the treatment of CRC. Although RA has shown significant efficacy in vitro, its clinical translation is hindered due to challenges related to bioavailability and safety. Therefore, it is necessary to promote the translation of RA from the laboratory to the clinic in the future through interdisciplinary cooperation, combining the multi-target advantages of natural compounds with modern drug delivery technologies. This strategy holds promise for improving the prognosis of CRC patients and sets a benchmark for developing natural drugs for other malignancies.