Citrus Flavonoids in Cancer Therapy and Inflammation Modulation

Citrus flavonoids, a diverse class of polyphenolic compounds abundant in the peels and juices of fruits such as oranges, lemons and tangerines, have attracted considerable interest for their dual roles in suppressing tumour development and tempering chronic inflammation. Principal members of this family, including nobiletin, tangeretin, hesperetin and naringin, exert anticancer effects by inducing programmed cell death, arresting cell‐cycle progression and inhibiting angiogenesis and metastatic spread. These compounds modulate key signalling cascades—among them NF-κB, PI3K/Akt and MAPK pathways—to downregulate pro-inflammatory cytokines and matrix metalloproteinases, thereby disrupting the tumour microenvironment and impairing malignant cell survival. Beyond direct cytotoxicity, citrus flavonoids enhance the efficacy of standard chemotherapeutic agents by reversing drug-efflux mechanisms and sensitising resistant cell populations. Their intrinsic antioxidant capacity further attenuates oxidative stress-driven inflammatory circuits that fuel cancer progression. Despite challenges in oral bioavailability, innovative delivery systems and structural modification of polymethoxylated flavonoids promise to bridge experimental observations and clinical translation. Collectively, the global significance of these natural products lies in their potential as adjuvants in multimodal cancer therapy and as modulators of chronic inflammation across diverse disease settings.

Research from Nature Portfolio

Recent studies have demonstrated that nobiletin directly interacts with the ATP-binding cassette transporter ABCB1, a principal mediator of multidrug resistance in cancer cells. By binding to the transmembrane domain of ABCB1, nobiletin inhibits efflux of chemotherapeutic agents such as paclitaxel and doxorubicin, leading to higher intracellular drug accumulation. Concomitant suppression of the AKT/ERK/Nrf2 signalling axis further sensitises resistant ovarian and lung carcinoma cells to cytotoxic agents. These findings underscore the promise of citrus flavonoids as chemosensitising adjuvants capable of overcoming transporter-mediated resistance.

Citrus Flavonoids in Cancer Therapy and Inflammation Modulation publication trend

The graph below shows the total number of articles in citrus flavonoids in cancer therapy and inflammation modulation across all publications each year (not limited to Nature Index journals).

Technical terms

Flavonoid: A plant‐derived polyphenolic compound with antioxidant and cell signalling properties.

Polymethoxyflavone: A flavonoid subclass bearing multiple methoxy groups, often enhancing lipophilicity and cellular uptake.

ABCB1 transporter: An ATP‐binding cassette efflux pump that extrudes chemotherapeutic drugs and contributes to multidrug resistance.

Apoptosis: Programmed cell death characterised by caspase activation, DNA fragmentation and membrane blebbing.

Angiogenesis: The formation of new blood vessels, a process fundamental to tumour growth and metastasis.

NF-κB: A transcription factor central to the regulation of inflammatory responses and cell survival.

References

1. A Scientometric Study to a Critical Review on Promising Anticancer and Neuroprotective Compounds: Citrus Flavonoids. Antioxidants (2023).
2. Nobiletin and Derivatives: Functional Compounds from Citrus Fruit Peel for Colon Cancer Chemoprevention. Cancers (2019).
3. Nobiletin enhances the efficacy of chemotherapeutic agents in ABCB1 overexpression cancer cells. Scientific Reports (2015).
4. Sinensetin: An Insight on Its Pharmacological Activities, Mechanisms of Action and Toxicity. Frontiers in Pharmacology (2021).