Cancer, a global health concern, continues to rise in incidence across both developing and developed nations, posing a significant threat to public well-being. Surprisingly, advancements in socioeconomic conditions often correlate with increased cancer rates. Nations like China, India, and Russia, experiencing a surge in cancer cases, grapple with mortality rates nearly double those in the UK or the USA. Factors such as vast geographical landscapes, burgeoning economies, aging populations, westernized lifestyles, environmental pollution, and unchecked communicable infections have collectively fueled this alarming rise in cancer incidence.
Cancer Projections:
A study by D'Souza et al. predicts a significant increase in cancer-related deaths, projecting numbers to reach 0.70 million by 2026. The leading contributors to this surge include population growth, a rise in the elderly population, urbanization, and globalization. Cancer mortality disproportionately affects women, with breast, cervix, and ovarian cancers accounting for 34% of all cancer-related deaths, while lung, oesophagus, prostate, and stomach cancers dominate male mortality statistics.
The Quest for Effective Cancer Treatment:
Despite the relentless pursuit of cancer treatment options over the years, successful outcomes remain elusive due to a lack of understanding of molecular signaling pathways and therapeutic targets. The existing armamentarium of over 50 chemotherapeutic drugs, developed since the 1940s, often comes with severe side effects, causing physical and mental trauma to patients. Consequently, there has been a continuous search for safer and more effective alternatives, leading to the exploration of the anticancer properties of phytochemicals.
Nature's Bounty: Saffron as a Promising Contender:
Nature has long been a source of therapeutic agents, and scientists have harnessed this potential by isolating modern drugs from traditional medicinal plant usage patterns. In the context of cancer prevention and therapeutics, plant-derived anticancer agents have demonstrated effectiveness. A notable example is saffron (Crocus sativus L.), a spice known for its various beneficial properties, including radical scavenging, antimutagenic effects, and immune modulation.
Pharmacological Properties of Saffron:
Crocus sativus L. has not only been valued as a flavouring agent but has also been the subject of pharmacological experiments showcasing its diverse benefits. Its aqueous or alcoholic extracts exhibit a wide range of activities, including anticonvulsant, antidepressant, antioxidant, anti-inflammatory, and anticancer properties. Chemical analysis has identified over 150 components in saffron, with crocin, crocetin, and safranal standing out as particularly powerful contributors.
Anticancer Properties of Saffron:
- Gastric Cancer:
Studies exploring saffron's potential in gastric cancer prevention have shown promising results. Saffron aqueous extract (SAE) demonstrated inhibitory effects on the progression of gastric tissue cancer in rats. Additionally, the active component crocin exhibited a dose- and time-dependent cytotoxic effect against gastric adenocarcinoma cells, inducing apoptosis and proving its anticancer potential.
- Colorectal Cancer:
Colorectal cancer (CRC) ranks as the third most common cancer in the Western hemisphere. A study by Aung et al. highlighted the inhibitory effects of Crocus sativus L. extract, particularly crocin, on the growth of colorectal cancer cells while sparing normal cells. This suggests a potential role for saffron in the treatment of colorectal cancer.
- Liver Cancer:
Hepatocellular carcinoma (HCC), ranking as the fifth most prevalent cancer and the third leading cause of cancer-related deaths, is witnessing a concerning rise in incidence. The majority of HCC cases are linked to chronic viral hepatitis, particularly hepatitis C virus (HCV). With over 170 million individuals globally affected by chronic HCV infection, there's an alarming increase in chronic hepatitis, cirrhosis, and HCC, leading to substantial morbidity and mortality. The escalating incidence of HCV infection poses a growing challenge, especially as the majority of HCC cases develop in the context of cirrhosis. The diagnosis and treatment of HCC have encountered significant changes and challenges in the last two decades. Traditional chemotherapy's limited effectiveness and the high recurrence rate of cancers underscore the urgency to identify new molecular targets and develop innovative treatments.
Several epidemiological studies emphasize an inverse association between fruit and vegetable consumption, natural antioxidants, and cancer risk. The stimulation of the immune system to destroy cancer cells or hinder their proliferation is recognized as a viable approach to cancer prevention.
Saffron has demonstrated noteworthy effects in countering diethylnitrosamine (DEN)-induced hepatic dyschromatic nodules and oxidative stress in rats. Additionally, saffron inhibited the elevation of pro-cancer markers and induced apoptosis in rat liver cells, highlighting its significant chemo-preventive effect against liver cancer[^25^, ^26^].
- Pancreatic Cancer:
Pancreatic cancer, ranking as the fourth leading cause of cancer death, presents a formidable challenge with a median survival of only 6 months and a discouraging 5-year survival rate of 3–5%. Despite advances in therapeutic modalities like surgery, radiation, and chemotherapy, the 5-year survival rate remains below 5%. The need for chemo-preventive treatments for high-risk individuals becomes crucial in the face of such bleak statistics.
Crocetin, a compound derived from saffron, has shown significant inhibitory effects on pancreatic cancer growth in both in vitro and in vivo studies. Administered to pancreatic cancer cells, crocetin demonstrated anti-proliferative effects, modulated cell cycle proteins, and induced apoptosis. In animal studies, crocetin orally administered after tumour development resulted in a substantial decrease in tumor growth, highlighting its potential as an antitumorigenic agent.
- Prostate Cancer:
Prostate cancer, with its high disease prevalence and challenges in diagnosis and therapy, necessitates effective prevention strategies. With controversies surrounding the risk/benefit ratio of prostate cancer screening, prevention becomes paramount. Compounds from natural sources, especially those with anticancer properties, are gaining attention. Several studies have established the correlation between vegetable, fruit, or plant-derived product consumption and reduced cancer incidence.
A study conducted by D'Alessandro et al. demonstrated the antiproliferative activity of saffron extract (SE) and crocin on various prostate cancer cell lines. Both SE and crocin exhibited a concentration-dependent inhibition of cell proliferation, inducing cell cycle arrest and apoptosis in prostate cancer cells. These findings suggest the potential use of saffron compounds as both chemopreventive and chemotherapeutic agents for prostate cancer management.
- Cervical, Ovarian, and Breast Cancer:
Cervical cancer's potential for chemoprevention lies in targeting high-risk individuals, particularly those with human papillomavirus (HPV) infection. Crocetin, a major component of saffron, displayed significant inhibitory effects on the proliferation of cervical, ovarian, and breast cancer cells in concentration-dependent manners. Cell cycle arrest and induction of apoptosis were observed, indicating the potential use of crocetin as a chemopreventive or chemotherapeutic agent for these types of cancer.
The significance of dietary and natural products in cancer prevention is underscored by numerous epidemiological studies correlating vegetable, fruit, and plant-derived product consumption with a reduced incidence of cancer.
- Skin Cancer:
The global incidence of skin cancer is on the rise, prompting increased efforts to comprehend the molecular mechanisms underlying skin carcinogenesis and identify substances for chemoprevention. Reactive oxygen species, generated by chemical carcinogens or UV irradiation, play a pivotal role in skin tumorigenesis. Evidence suggests that cellular cytoprotective proteins, encompassing antioxidants and phase-2 detoxification enzymes, may safeguard against skin carcinogenesis.
Contemporary cancer chemoprevention, viewed as a promising strategy, focuses on intervening in the processes of carcinogenesis using natural products. Phytochemicals, possessing antioxidant, antimutagenic, anticarcinogenic, and carcinogen detoxification properties, are considered effective chemo preventive agents. Numerous studies have investigated phytochemicals with potential molecular targets affecting cellular processes like inflammation, immunity, cell cycle progression, and apoptosis, identifying several candidates beneficial for preventing skin cancer.
The impact of saffron's aqueous infusion on skin papillogenesis/carcinogenesis in mice, induced by 7-12 dimethylbenz[a]anthracene (DMBA) and promoted with croton oil, demonstrated marked inhibition in papilloma formation during pre- and post-initiation periods. Saffron's modulatory effects on Phase II detoxifying enzymes, such as glutathione-S-transferase (GST) and glutathione peroxidase (GPx), as well as catalase (CAT) and superoxide dismutase (SOD), were attributed to this suppression.
- Lung Cancer:
Lung cancer, a leading cause of global cancer-related mortality, is often diagnosed at an advanced stage, limiting curative treatment options. Crocetin, a derivative from saffron, has shown potential in cancer chemoprevention. Evaluations against lung cancer-bearing mice, both in pre- and post-initiation periods, revealed crocetin's normalization of elevated lipid peroxidation levels and marker enzymes. Crocetin administration mitigated pathological changes in cancerous animals, demonstrating its potential therapeutic efficacy.
Studies by Samarghandian et al. underscored saffron's potential in inducing cytotoxic and apoptotic effects in lung cancer cells (A549). Saffron administration reduced A549 cell proliferation in a dose- and time-dependent manner, enhancing the percentage of apoptotic cells. The observed anticancer activity was attributed to saffron's inhibition of cell proliferation and induction of apoptosis through caspase-dependent pathways.
The ethanolic extract of saffron also exhibited concentration- and time-dependent reduction in cell viability in carcinomic human alveolar basal epithelial cells (A549). The extract's proapoptotic effects in a lung cancer-derived cell line suggest its potential as a chemotherapeutic agent against lung cancer.
- Leukemia:
Research findings indicated that crocin suppressed HL-60 cell proliferation, induced apoptosis, and caused cell cycle arrest in a concentration and time-dependent manner. Crocin administration reduced tumor weight and size of HL-60 xenografts in mice, downregulated Bcl-2 expression, and upregulated Bax expression. Additionally, safranal and crocin exhibited cytotoxic responses to K562 cells (human chronic myelogenous leukemia cells), suppressing Bcr-Abl gene expression and protein tyrosine kinase activity. Crocin also demonstrated mild cytotoxic effects on the human T-cell leukemia cell line MOLT-4, potentially mediated through increased DNA fragmentation.
- Anticancer Toxicity:
Anticancer treatments, including anthracyclines, induce cardiotoxicity by releasing reactive oxygen species (ROS). Saffron perfusion during electrolysis significantly recovered myocardial function, trapping ROS and alleviating myocardial architectural distortions. However, saffron was less effective against doxorubicin (Doxo), suggesting other mechanisms contribute to Doxo cardiotoxicity.
- Toxicology:
The crocin principle in saffron demonstrated high efficacy with no major toxicity in experimental models. Safranal showed low toxicity in acute intraperitoneal routes and was nearly nontoxic in acute oral administration in both mice and rats. Subacute toxicity resulted in changes in some haematological and biochemical parameters but did not exhibit toxic effects on the heart, liver, and spleen. Noteworthy pathological changes were observed in the kidney and lung.
Discussion and Conclusion:
Cancer, a significant public health concern, necessitates ongoing efforts to explore novel agents and therapies for enhanced survival. Traditional and modern medicine integration, especially utilizing natural compounds, offers potential solutions. Carotenoid-rich saffron, particularly crocin and crocetin, has demonstrated anticancer effects through multiple mechanisms, including modulation of carcinogen metabolism, cell growth regulation, antioxidant activity, and immune modulation. With promising evidence from human, animal, and cell culture studies, saffron and its components present opportunities for effective cancer chemoprevention and treatment with minimal side effects.
Traditional medicine, such as Ayurveda, practiced for thousands of years, can be integrated with modern medicine to improve cancer treatment. The exploration of alternative or synergistic anticancer drugs is crucial for overcoming the limitations of existing chemotherapeutic agents.
Given its significance in therapy and the economy, along with its abundant natural presence and widespread use in traditional medicine, saffron emerges as a diverse and accessible platform for exploring phytochemical-based drug discovery. To harness this potential fully, it is crucial to amalgamate traditional knowledge, chemical characteristics, and pharmacological profiles. Future research efforts should be directed towards a more concentrated exploration through clinical studies and precise phytochemical delineation.
While existing results and literature strongly suggest saffron's potential as a cancer chemo preventive agent in clinical trials, a more robust focus on well-designed trials using the reduction of cancer incidence as the primary endpoint is necessary for obtaining direct evidence of its anticancer efficacy. Thus, it is recommended that upcoming research endeavours delve into defining saffron's potential role as an effective anticancer and chemo preventive agent through rigorous clinical trials. Despite convincing in vitro data, the ultimate confirmation of saffron's utility in our anti-cancer arsenal awaits well-executed human clinical trials.
Encouraging outcomes from both in vitro and in vivo experiments could pave the way for identifying optimal drug combinations involving these phytochemicals and synthetic antineoplastic drugs. This opens up new possibilities, moving beyond conventional antineoplastic drug combinations, and suggests potential interventions in clinical settings.
References:
https://www.sciencedirect.com/science/article/pii/S2225411014000194#fig1
