Natural essential oils as a new therapeutic tool in colorectal cancer

Colorectal cancer (CRC) is a devastating disease with a high incidence and mortality rate, accounting for more than 10% of all cancer death in 2020, being the third most common cancer in men and the second in women [1, 2]. According to the International Agency for Research on Cancer, in 2018, the global cancer burden is estimated to have risen to 18.1 million new cases and 9.6 million deaths. CRC is the second largest cancer worldwide with 881,000 deaths in 2018 [3‐5]. Studies show that approximately 90% of colorectal cancer cases occur in people over the age of 50 and the number of patients diagnosed with CRC exceeds that of patients diagnosed with lung cancer. CRC has a high rate of treatment success when it is detected in its early stages [6]. Thus the 5-year survival rate is over 90% in early-diagnosed colorectal cancer, but only 40% of tumors are found at a localized stage and approximately 56% of colorectal cancer patients die from the tumor. In stage IV, survival is low, only 14–16% at 5 years [7]. CRC is a type of cancer that affects colon or rectum cells and normally starts on the inner lining of these tissues, where the pathologist can find the so-called polyps [8]. Even if polyps are not strictly malignant, with time they can sometimes enlarge, grow and spread originating cancer. The most common form of CRC is adenocarcinoma and this review analyzed only this kind of tumor, not considering less frequent forms of cancer affecting the colon and rectal tissues, such as carcinoid tumors, gastrointestinal stromal tumors (GISTs), lymphomas, and sarcomas [9, 10]. In general, CRC does not cause symptoms at the initial stages, even if small blood loss, fatigue, lack of appetite, anemia, weight loss, stubborn constipation, alternating with diarrhea can be present [11]. The diagnosis of CRC is based on an accurate anamnesis, followed by blood tests with the research of carcinoembryonic tumor marker (CEA), digital rectal examination and colonoscopy with biopsies. In addition, ultrasound, computed tomography (CT) and magnetic resonance imaging can be used to assess the extent of the tumor itself and the presence or absence of distant metastases [12]. More recently, clinicians are beginning to use the results of the molecular profile of CRC from biopsy, as it can serve to better define the prognosis and therapy of this neoplasia [13]. The therapeutic strategy is essentially based on surgery, which can be assisted by chemotherapy and radiotherapy, alone or combined, adjuvant or neoadjuvant. Moreover, targeted therapy and immunotherapy are two recent therapeutic tools for the management of aggressive, advanced or metastatic CRC [14, 15]. Nonetheless, these strategies have numerous adverse side effects, and as a result, new adjuvant therapies in the treatment of cancer have been sought, the naturally bioactive compounds being known as potential anticancer adjuvant and complementary agents [16‐19]. The study of natural products has always guided the field of applied pharmacology [20]. They have played a key role in drug discovery, especially for cancer and infectious diseases [21, 22]. In the area of cancer, since the 1940s, more than 50% of the active molecules are unaltered or derivative natural products of different origins (plant, animal and microbial) [16, 23]. Among these, some examples are paclitaxel (Taxol^®), vincristine (Oncovin^®), vinorelbine (Navelbine^®), teniposide (Vumon^®) and various water-soluble analogues of camptothecin (e.g. Hycamtin^®) [24‐26]. After a decline in the pharmaceutical industry's search for natural products from the 1990s onwards due to technical barriers to screening, isolation, characterization and optimization, in recent years, technological and scientific development has revitalized the interest in them [27, 28]. According to Newman & Cragg [26], natural products still offer the best potential for discovering new compounds that can lead to effective agents in a variety of human diseases. Essential oils, complex mixtures of volatile organic compounds extracted from plants by steam distillation, dry distillation or a suitable mechanical process without heating, possess biological and pharmaceutical properties including anticancer activity [29]. Various types of malignancies are reported to be lowered after treatment with essential oils [30]. The current status of knowledge regarding their potential in the treatment strategies of CRC, the second deadliest (about 1 million per year) and third most commonly diagnosed cancer in the world (about 2 million cases in 2020) [1], is covered in this review.

Various EOs have been studied in many types of experimental models in the search for new treatments for colon cancer with very promising results [16, 20] (Additional file 1). EOs exhibit a wide range of bioactive effects like cytotoxicity, antiproliferative, and antimetastatic effects on cancer cells through various mechanisms of action [49]. It has been demonstrated that EOs possessed, for the most part, a prodigious activity directed against cancer cells [45]. In the case of CRC, the effect of EOs has been analyzed in vitro studies on human colon cancer cell lines such as HT-29, Caco-2, SW480, and HCT-116, among others. HCT-116 cells have been the most studied since they are classified as a cell line model to study the molecular mechanisms involved in tumor metastasis [50]. The EOs' bioactive compounds against colorectal cancer models are summarized in Table 1 and Fig. 1.

The synergy between different compounds is a sought-after effect in the fight against cancer. Such effect of the essential polyphenolic compounds of curcumin, the EO of turmeric (ETO-Cur), and the tocotrienol-rich fraction (TRF) of the vitamin E isomers has been evaluated in HT-29 and HCT-116 cells. Indeed, the combined treatment, especially for ETO-Cur and TRF, showed synergistic potential in the 2 cell models. Similarly, in in vivo studies, HCT-116 cells xenograft in SCID mice were treated by ETO-Cur and TRF, which synergically acted to inhibit tumor volume. Moreover, even changes in microbial diversity were observed in xenograft mice treated with such EOs combination [173].

Various studies have reported that TQ could enhance anti-cancer potential when co-administered with several chemotherapeutic agents while reducing their toxic side effects [175]. Different compounds (menthol, trans-anethole) were investigated for the preparation of oil/water microemulsions for the delivery of methotrexate, and the ability of methotrexate-loaded microemulsions to inhibit cancer cell growth. Menthol and trans-anethole EOs led to cytotoxic microemulsions decreasing HeLa cells proliferation by MTT assay concluding that the oily component could play a role in the efficacy and safety of the microemulsions (for comparison α-tocopherol based-formulations showed opposite effects with increased cell proliferation) [176]. EO from the leaves of M. rubra also demonstrated an antiproliferative effect on Caco2 cells, with strong prooxidative effect. In addition, this EO was able to improve the antiproliferative and prooxidative activity of doxorubicin enhancing intracellular and nuclei accumulation, as previous described [147].

A limitative aspect of using the EOs in CRC management is represented by variable concentrations of bioactive compounds. Many factors, including ecological and geographical conditions influence to the quality and quantity of EOs. The chemical composition and biological activities of EOs depend on various factors such as habitat, climatic conditions, seasonality, cultivation and harvesting and conservation practices, the type of soil, the different extraction procedures [177‐180] as well as a substantial variability based on the part of the plant used for the extraction of EO. Altitude is an important factor affecting yield, composition, and biology of plant extracts. Satureja thymbra L. EO showed increased cytotoxic activity at an altitude of 661 m if compared to the same EO collected at 156 m above sea level. This result was obtained using the sulforhodamine B assay on HCT-116 colon cancer cells with an IC₅₀ of 2.45 ± 0.21 μg/mL. In this case, the EO composition was prevailed by carvacrol (14.30%) [181]. Another important therapeutic limitation derives from the fact that it is not known exactly and completely the pharmacokinetic profiles of the essential oils, and due to their hydrophobic nature EOs can lead to poor bioavailability and pharmacodynamics issues.

Clinical challenges derived from the search for a natural therapy that includes EOs has led to attempts to find methods for administering the extracts. To overcome these issues, researchers explored the possibility to load nano-carriers with EOs, individually or combined with conventional chemotherapeutic agents. For example, A Carum carvi L. oil nanoemulsion system was tested on HT-29 cells, whereas it demonstrated a cytotoxic effect and apoptosis induction by increased gene expression of caspase-3. Besides, the authors suggested that the use of dietary supplements with nanoemulsions could potentially decrease the risk of cancer and that more research was needed to confirm this hypothesis [182]. This approach of drug delivery however has been poorly studied in CRC and EOs thus leaving the possibility to go down this route, at least in preclinical models. In order to improve the anticancer therapeutic potential and reduce the toxicity of bioactives compounds, new nanopharmaceutical forms for target transport such as nanoparticles, liposomes, nanocapsules, niosomes should be developed and researched [21, 22, 163, 183]. Alternatively, EOs can be combined with other more bioavailable compounds in order to harness their impact on human organism. For example, EOs can be used together with other plant natural derived products to search for an additive or a synergistic effect. Nonetheless, this combination scheme should be carefully evaluated, as sometime novel compounds put inside in a complex organism can lead also to antagonistic effects, an activity that need to be avoided. Despite remarkable anticancer activity of EOs in CRC and cancer in general, clinical trials that face the challenge of using such preparations in humans are still lacking. It is hoped that this gap will be rapidly filled in and that new works will explore the superb effects of EOs in CRC.

Essential oils have been used in alternative medicine for a very long time, due to the healing properties that have been studied and demonstrated. Numerous experimental pharmacological studies have shown that they can inhibit the development of cancer and deserve to be used in prevention and even as adjuncts to classical chemotherapy. Therapeutic strategies to fight against CRC relay on surgery, radiotherapy, immunotherapy, and chemotherapeutic agents. EOs, defined as volatile chemical molecules from plants, can be potentially inserted in the last category of curative tools for the treatment of cancer. Though numerous advancements have been reported in surgery and chemotherapy in the last decades leading to progression of patient time survival and even in the increase of clinical conditions of affected patients, the death rate of CRC is still worrying healthcare system worldwide. This updated review showed scientific evidence on the potential anticancer effect of EOs in CRC. EOs can exhibit cytotoxic effects on living cells depending on type and concentration. In eukaryotic cells, EOs can act as prooxidants affecting inner cell membranes and organelles such as mitochondria. In some cases, changes in intracellular redox potential and mitochondrial dysfunction induced by EO can be associated with their capacity to exert antigenotoxic effects. EOs can interfere with several molecular targets in a pleiotropic fashion, but undeniably the cytotoxic activity of EOs is based on their individual components. In general, EOs (due to their lipophilic properties and low molecular weights) can cross cell membranes altering the phospholipid layers, increasing membrane fluidity, and leading to leakage of ions and/or other cytoplasmic content, thus inducing ATP reduction, alteration of pH gradient and loss of mitochondrial potential. In the light of these results, EOs can be a new therapeutic window and a potential adjuvant chemotherapy of CRC.