Cancer remains a formidable global health challenge, ranking as the second leading cause of death worldwide and poised to surpass heart disease in the coming years. The uncontrolled proliferation, heightened differentiation, and immortality exhibited by cancer cells underscore the urgency of finding effective treatments. Among the promising candidates for cancer therapy, crocin, a water-soluble carotenoid pigment extracted from the stigmas of Crocus sativus L., has garnered significant attention.
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Introduction of Crocin
Crocin is a water-soluble carotenoid pigment found in the stigmas of Crocus sativus L. There are four chemical analogues of crocin, known as crocins 1-4. These analogues are glycosides of trans-crocetin, a derivative of carotenoids. Crocin 1, also known as alpha-crocin or crocetin digentiobiose ester, is the most abundant crocin in saffron and has been extensively researched for its pharmacological effects. Crocin has the chemical formula C44H64O24 and is the primary reddish-yellow pigment in saffron.
Biological Activities of Crocin
The multifaceted biological activities of crocin encompass antioxidative effects, anti-inflammatory properties, and analgesic impacts. Crocin has been reported to physically interact with various cellular proteins, including structural proteins, membrane transporters, and enzymes involved in adenosine triphosphate (ATP) synthesis. This interaction extends to key cellular processes such as redox homeostasis and signal transduction. Notably, crocin has been shown to enhance glutathione synthesis, fortifying the cell's defense against oxidative stress.
The anti-inflammatory effects of crocin manifest through its dual inhibitory action against cyclooxygenase 1 and 2 enzymes, as well as prostaglandin E2 production. Crocin's impact on inflammation is further evidenced by its ability to inhibit leukocyte infiltration, ICAM-1, and TNF-α expression levels. It also modulates signaling pathways, such as ERK-MAPK/NF-kB/STAT1, showcasing its broad anti-inflammatory potential.
Beyond its antioxidative and anti-inflammatory attributes, crocin extends its influence on neurological aspects. With anti-depressant-like actions, crocin enhances the levels of CREB protein, BDNF, and VGF in the hippocampus. It also demonstrates protective effects against memory impairment induced by various stressors, showcasing its potential in mitigating neurodegenerative conditions.
Molecular Mechanisms of Crocin in Specific Cancers
Colorectal Cancer
Colorectal cancer (CRC) is a prevalent malignancy within the gastrointestinal tract, ranking third after gastric and esophageal cancers. Research has shown that crocin, a natural compound, significantly reduces the proliferation rate in various human colorectal cancer cell lines, with notable effectiveness on HCT-116 cells. Chronic inflammation has been identified as a crucial factor in tumor development, particularly evident in CRC, where a close correlation between chronic inflammation and carcinogenesis exists.
The nuclear factor kappa-light-chain-enhancer of activated (NF-kB) transcription factor, a hallmark of inflammatory responses frequently found in tumors, plays a significant role in the progression of various human cancers. Non-steroidal anti-inflammatory drugs (NSAIDs) or glucocorticoids are known to exert their anti-cancer effects through the inhibition of NF-kB. Another factor contributing to inflammation is Nrf2, a transcription factor regulating antioxidant elements, protecting organs against oxidative damage induced by inflammation and injury.
Studies suggest that disruption of the Nrf2 gene increases susceptibility to colitis and colon carcinogenesis. Crocin has exhibited anti-inflammatory effects through the inhibition of NF-κB factor. It has also shown the ability to suppress colitis, possibly by inhibiting inflammation.
Breast Cancer
Breast cancer, the leading cause of cancer mortality in women globally, involves genes categorized by their penetrance of clinical manifestation. Crocin demonstrates apoptotic effects on breast cancer cells, inducing caspase activation and disrupting the mitochondrial membrane potential. Combining crocin with hyperthermia enhances its apoptotic effect, suggesting a potential synergy with conventional chemotherapy. Crocin also suppresses cyclin D1, a key player in breast cancer development, and may inhibit cancer cell division through microtubule stabilization.
Lung Cancer
Lung cancer, a leading cause of global cancer-related mortality, comprises non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Crocin decreases proliferation, induces apoptosis, and enhances sensitivity to chemotherapy in lung cancer cells. Prostate cancer, a major cause of male cancer-related deaths, experiences antiproliferative effects from crocin, inhibiting cyclin D1 expression and inducing apoptosis. Crocin also reverses epithelial-mesenchymal transition (EMT), a process associated with increased tumor cell motility.
Prostate Cancer
Prostate cancer, a significant cause of male mortality, exhibits slow growth and metastasis. In prostate cancer, crocin's antiproliferative effects are mediated through cell cycle modulation and induction of apoptosis. Notably, crocin inhibits the expression of cyclin D1, a key player in prostate cancer development. Additionally, crocin's impact on reversing epithelial-mesenchymal transition (EMT) features in aggressive prostate cancer cells highlights its potential to suppress metastatic behavior.
Liver Cancer
Hepatocellular carcinoma (HCC) is the primary form of liver cancer, often associated with factors such as viral infections and aflatoxin exposure. Crocin has been found to inhibit cell proliferation, induce apoptosis, and suppress NF-kB in hepatocytes. Its inhibition of telomerase activity in HCC cells contributes to its potential anti-cancer effects.
Cervical Cancer
Cervical cancer is a prevalent neoplastic disease affecting women worldwide. Crocin has demonstrated anticancer effects on human cervical cancer, inducing apoptosis and cytotoxicity in HeLa cell lines. Crocin liposomal forms have shown enhanced cytotoxic effects compared to free crocin, making it a potential candidate for drug delivery applications.
Tongue Squamous Cell Carcinoma
Crocin exhibits a proapoptotic effect and reduces cell viability, growth, and nucleic acid contents in human tongue squamous cell carcinoma cell lines. Its impact on DNA synthesis and cell division rates suggests its potential as an inhibitor of cancer progression.
Hematologic Neoplasms
Leukemia, characterized by clonal proliferation of blood progenitor cells, has been studied for its response to crocin treatment. Crocin has shown anti-proliferative and pro-apoptotic effects on leukemia cells in vitro and in vivo. It also exhibits potential as a clinical agent for the treatment of T-lineage acute lymphoblastic leukemia (T-ALL) by inhibiting Bcl-2 and promoting Bax gene expression.
Ovarian Cancer
Ovarian cancer, a significant cause of gynecological cancer-related deaths, often exhibits multidrug resistance. Crocin has demonstrated cytotoxic activity in ovarian cancer cell lines, reducing cell proliferation, and suppressing the expression of multidrug resistance-associated proteins (MRPs). Its ability to induce apoptosis and modulate the cell cycle suggests potential for ovarian cancer treatment.
Pancreatic Cancer
Pancreatic cancer, one of the most lethal malignancies, has seen the cytotoxic effects of crocin demonstrated in vitro. Crocin induces apoptosis and G1-phase cell cycle arrest in pancreatic cancer cells, suggesting its potential as a treatment option.
Gastric Cancer
Gastric cancer, arising from neoplasia in the gastric mucosa, has been studied for its response to crocin treatment. Crocin significantly decreases cell viability in gastric adenocarcinoma cells, inducing apoptosis and inhibiting tumor growth. Its impact on caspase activities and the Bax/Bcl-2 ratio further supports its potential as an anti-cancer agent.
Conclusion
The multifaceted biological activities of crocin, coupled with its specific molecular mechanisms in targeting various cancers, highlight its potential as a promising therapeutic agent. From modulating inflammation to inducing apoptosis and regulating key signaling pathways, crocin demonstrates a nuanced approach to cancer treatment. As research continues to unravel the intricacies of crocin's anticancer properties, it holds promise as a valuable addition to the armamentarium against this formidable disease. Further clinical studies and translational research will be crucial in harnessing the full therapeutic potential of crocin in the fight against cancer.
References
- Veisi A., et al. Role of crocin in several cancer cell lines: An updated review. Iranian Journal of Basic Medical Sciences. 2020, 23(1): 3.
- Bao X., et al. Advances on the anti-tumor mechanisms of the carotenoid Crocin. PeerJ. 2023, 11: e15535.
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