Garcinol in gastrointestinal cancer prevention: recent advances and future prospects

Cancers are characterized by aberrant cell proliferation that can infiltrate or spread to other bodily regions. Cancer continues to rank among the world’s most terrible diseases, even with ongoing improvements in diagnostic and treatment techniques (Cao et al. 2021). Currently, which therapeutic methods are used depends on the type and stage of the malignancy. Among the various treatment options include chemotherapy, radiation therapy, targeted therapy, and surgery (Kaur et al. 2023). According to projections, there will be approximately 26 million additional cases of cancer by 2030. As per 2018 report, there were 3.4 million associated fatalities and an anticipated 4.8 million new cases of gastrointestinal (GI) malignancies worldwide (Wang et al. 2024). In the world, 1 in 4 cancer diagnoses and 1 in 3 cancer-related fatalities are caused by gastrointestinal (GI) cancers. Numerous genetic and environmental factors may influence the development and risk of gastrointestinal malignancies, according to studies (Lu et al. 2021). Natural remedies have several special advantages in modern medicine as compared to conventional chemotherapeutic medications. These advantages include low cost, low toxicity, high patient acceptance rate and minimal side effects.

Natural phytochemicals are a rich source of innovative medications for a wide range of illnesses. It has been demonstrated that these substances, which are thought to be safe for human usage, alter important cellular signaling pathways that cause them to have anticancer properties (Sheikh et al., 2020). Garcinia indica/ Garcinia cambogia fruit rinds naturally contain a polyisoprenylated benzophenone called garcinol. Numerous investigations using cancer cell lines and experimental animal models have demonstrated the anti-cancer effects of garcinol (Aggarwal et al. 2020; Noreen et al. 2023). Furthermore, garcinol has been demonstrated to have powerful anticancer effects, activating apoptosis and autophagy, and lowering tumor cell resistance to chemotherapeutic agents in gastric cancer. Old conventional and newly developed anticancer agents face challenges due to the development of drug resistance in cancer cells, which is intricately linked to epigenetic alterations. Epigenetic changes (such as DNA methylation and histone acetylation), decrease the expression of target enzymes while increasing the expression of drug export pumps, resulting in drug resistance (Asano 2020).

Cancer immune evasion is yet another significant challenge in cancer treatment. Tumors cells use mechanisms to block immune checkpoints, such as PD-1, PD-L1, and CTLA-4, and further block proliferation and activation of T-cell. They also attract immunosuppressive cells to form a protective environment around themselves. Additionally, within the tumor microenvironment (TME), tumors accumulate specific metabolites and signaling factors that inhibit function of immune system. They also reduce the availability of vital nutrients to immune cells, further weakening the immune response (Dutta et al. 2023; Wang et al. 2023; Kim and Cho 2022; Kallingal et al. 2023). Metabolic reprogramming, including the Warburg effect, enables cancer cells to survive under various conditions. Cancer cells frequently develop resistance to medicines by processes such as drug efflux and changes in target genes, complicating treatment even more (Liberti and Locasale 2016).

This review delves into the intricate mechanistic insights of the anticancer aspects of garcinol, providing an up-to-date exploration of recent trends and advancements in its research and application. This comprehensive review aims to offer a holistic comprehension of garcinol’s therapeutic potential and its diverse implications for drug discovery and development.

We conducted comprehensive searches using PubMed, Scopus, and Google Scholar to gather relevant studies. Relevant full-length articles published in peer-reviewed journals from January 2005 to April 2024 were included. Followings were inclusion and exclusion criteria’s.

In a chemical way Garcinol, a polyisoprenylated benzophenone (Fig. 1), is naturally occurring phytochemical found in the plants Garcinia cambogia, also known as Malabar tamarind, and Garcinia indica, which belong to the Clusiaceae family and are commonly known as Kokum (Fernando et al. 2019). In current methods of methanol / and ethyl acetate extraction using chopped dried kokum plums produces good yields of garcinol (up to 5 g from 500 g dried kokum plums). Subsequently, yellow needles like crystal with a melting point of 132 °C are produced by crystallizing the concentrated eluate of hexane fraction through column chromatography of the concentrated ethyl acetate extract (silica gel 60, ethyl acetate/hexane 1:2) (Schobert and Biersack 2019; Ullah and Ahmad 2016). Another effective large-scale isolation technique was developed by washing the Garcinia indica fruits with water to remove the hydroxycitric acid and extracted using methanol. The methanol extract loaded on Celite was eluted using hexane. Finally, the extract of hexane was separated using column chromatography (Schobert and Biersack 2019).

Chemists have also recently extracted garcinol from the fruits of Garcinia multiflora, a South Chinese medicinal plant (Hemshekhar et al. 2011; Liu et al. 2017). 500 mg of garcinol were extracted from 5.2 kg of dried G. multiflora fruits. Garcinol was obtained by extracting the powdered dried fruits of G. multiflora using 95% ethanol and petroleum ether using column chromatography on silica gel followed by recrystallization (Liu et al. 2017). Additionally, plants belonging to the Garcinia species G. morella, G. yunnanensis, G. xanthochymus, and G. travancorica were shown to contain and yield Garcinia ethanol (Choudhury et al. 2018; Zheng et al. 2017; Jackson et al. 2015; Anu Aravind et al. 2016). Furthermore, it was recently discovered that the stem bark of the Garcinia species, G. buchananii, has also garcinol presence (Stark et al. 2015).

Garcinia indica is the source of Garcinol. Assessing its safety is essential for therapeutic applications (Lim et al. 2021). Various areas of safety were examined in studies. These comprise the following: potential against inflammation, potential against cancer, reproductive toxicity, developmental toxicity, acute toxicity, and repeated dosage toxicity (Majeed et al. 2018). The acute and sub-chronic toxicity of 40% standardized garcinol was evaluated in rodents. This research had OECD criteria in mind. The toxicity of carcinol to rodents was found to be minimal. On clinical symptoms, behavior, development, reproduction, or histology, no negative consequences were observed. The hazardous nature of semisynthetic derivatives of garcinol (Beerwala et al. 2024). In a preclinical model, they investigated the metastasis of pulmonary melanoma. In mice in good health, the compounds had a beneficial effect without generating systemic damage. The anti-cancer and anti-inflammatory properties of Garcinol safety (Liu et al. 2015). They looked into how the inflammatory Aquaporins are modulated by Garcinol. It successfully inhibited the generation of proinflammatory cytokines in cell culture models. Garcinol inhibits alpha-amylase, indicating that Garcinia indica extract may have promise as an antidiabetic drug, according to research conducted in vitro and in silico (Kalita and Das 2024).

Preclinical research has shown encouraging results, however, the toxicity profile of Garcinol is still unknown to experts. Its safety for clinical application has to be further investigated (Majeed et al. 2018). Garcinol has an excellent safety profile according to preclinical research, and animal experiments have shown no significant harm. Nevertheless, more investigation is required by scientists to completely comprehend the clinical safety and treatment potential of ganciclovir for inflammatory and cancerous diseases. This includes pharmacokinetic investigations and clinical trials (Butnariu et al. 2022).

Nanotechnology makes the delivery of Garcinol more effective in the battle against gastrointestinal malignancies. Garcinol, an anti-cancer bio-chemical for GI cancers (Table 1), is derived from Garcinia indica. However, Garcinol has difficulties getting to tumor effectively. Nanoparticles engineered for targeted delivery of specific compound (specially for tumor microenvironment remodelling) have emerged as promising tools in cancer treatment (Lu et al. 2024). Garcinol is wrapped with nanoparticles, which enhance its solubility and target tumor locations (Jacob et al. 2021). In combination with other anti-cancer agents, garcinol produces a synergistic effect. Nanoparticles enable controlled release with specific targeting of garcinol, further potentiating its effect on cancer cells (Aggarwal et al. 2020). Controlled release of Garcinol, specifically in the colon, is made possible by using pH-responsive nanoparticles. This minimizes side effects across the body and offers targeted treatment for gastrointestinal tumors (Brito et al. 2022). As a result, cancer cells can be actively targeted, improving the specificity and effectiveness of treatments. For better use, Garcinol may be encapsulated in nanoparticles which can shield it from the body’s breakdown and make it easier to absorb by the body (Li et al. 2023). Combine effect of peptides and nanoparticles enhance their ability to target specifically tumor cells (Dai et al. 2024). Exosomes are small, membrane-bound vesicles released from cells into the extracellular environment. As carriers of anti-tumor agents, they can modify the tumor microenvironment, results in significant change in cancer cell proliferation and migration (Paskeh et al. 2022). We have also looked into possible synergistic benefits among garcinol and other phytochemicals, like curcumin, along with garcinol and the cancer drugs currently available for treatments in pancreatic cancer cell lines, such as gemcitabine (Kopytko et al. 2021). Using a combinatorial approach, the findings show that garcinol and curcumin suppress Pancreatic cancer cells, Panc 1 and BxPC3, more so than either drug alone by increasing the induction of apoptosis (Rizvi et al., 2024). Using different doses and incubating periods, garcinol and gemcitabine were given alone and combined with human pancreatic cancer cell lines, BxPC 3 and Panc-1, that contained the wild-type and mutant K-ras genotypes, respectively (Mane et al. 2012). This treatment is intended to observe the level of apoptotic cell death and growth reduction. Compared to the individual therapies, the combination of garcinol and gemcitabine demonstrated a significant decrease in cell proliferation and an increase in apoptosis. Additionally, garcinol downregulated NF-κB, VEGF, Il 8, MMP-9, and activated PARP cleavage in concert with gemcitabine to promote its activity (Zheng et al. 2020). This highlights garcinol’s potential greater in combinatorial treatment approaches. However, its clinical translation faces several challenges. Among the most significant is their poor bioavailability which could be improved by their solubility and targeted delivery enhancement through nanotechnology (Ahmad et al. 2011). In addition, because interactions between various chemopreventive agents can produce different results due to their diversity, achieving the combined effect is still difficult. Understanding and optimizing these interactions requires extensive preclinical and clinical studies (Hong et al. 2007).

The evidence presented highlights the potential of garcinol as a promising therapeutic agent against gastrointestinal cancers. Studies demonstrate its ability to inhibit cancer cell proliferation, induce apoptosis, and suppress metastasis through various molecular mechanisms. Moreover, its low toxicity and high patient acceptance rate make it an attractive candidate for cancer treatment. It enhances chemotherapy effectiveness, exhibits anti-inflammatory effects, inhibits angiogenesis, and has a favorable safety profile in preclinical studies. These multi-targeted actions suggest Garcinol’s potential in both therapeutic and preventive oncology (Behera et al. 2016). However, challenges such as poor bioavailability and delivery issues need to be addressed. Future research should focus on optimizing garcinol’s delivery, possibly through nanotechnology, to enhance its efficacy and minimize side effects. Additionally, investigating synergistic combinations with other phytochemicals or conventional cancer drugs could lead to more effective treatments. Clinical trials are needed to validate garcinol’s efficacy and safety in patients. Additionally, further exploration of garcinol’s mechanisms of action and its effects on different types and stages of gastrointestinal cancers would provide valuable insights.