Essential Oils in Cervical Cancer: Narrative Review on Current Insights and Future Prospects

Cervical cancer is a prevalent and often devastating disease affecting women worldwide. Traditional treatment modalities such as surgery, chemotherapy, and radiation therapy have significantly improved survival rates, but they are often accompanied by side effects and challenges that can impact a patient’s quality of life. In recent years, the integration of essential oils into the management of cervical cancer has gained attention. This review provides an in-depth exploration of the role of various essential oils in cervical cancer, offering insights into their potential benefits and the existing body of research. The review also delves into future directions and challenges in this emerging field, emphasizing promising research areas and advanced delivery systems. The encapsulation of essential oils with solid lipid nanoparticles, nanoemulsification of essential oils, or the combination of essential oils with conventional treatments showed promising results by increasing the anticancer properties of essential oils. As the use of essential oils in cervical cancer treatment or management evolves, this review aims to provide a comprehensive perspective, balancing the potential of these natural remedies with the challenges and considerations that need to be addressed.


Introduction
Cervical cancer is the most common gynecologic malignancy and is the fourth most frequent cancer type among women globally, making it one of the main causes of mortality [1].In 2020, it was estimated that 604,000 new cases and 342,000 deaths occurred among women due to this cancer [2].Cervical cancer death rates differ from nation to nation, and about 90% of these occur in low-and middle-income countries due to limited access to preventive measures [2].In addition, cervical cancer is always asymptomatic until it progresses to a severe phase.According to the World Health Organization [3], there is a lack of access to treatments for malignant lesions, such as chemotherapy, radiation, and surgery, which leads to an increase in the mortality rate from cervical cancer in these countries.The most common signs of cervical cancer include severe pelvic discomfort, extreme weight loss, and anorexia, as well as any abnormal discharge from the vagina (increased menstrual bleeding, bleeding between the two menstrual cycles, and post-menopausal bleeding) [4].
Surgery (e.g., radical hysterectomy and pelvic lymphadenectomy), radiation, and chemotherapy are the most often employed treatments for cervical cancer [5].All these treatments, including chemotherapy, nevertheless, have exhibited serious adverse effects like bleeding, organ impairment, and blood clots [4,6].
In order to overcome the undesirable side effects of modern treatment, an external supply of alternative medicine may be necessary to protect the organ from harmful effects.

Human Papillomavirus as Risk Factors of Cervical Cancer
A strong association between HPV and cervical squamous cell cancer has been reported since the early 1980s [10,11].HPV is a member of the Papillomaviridae family and one of the most prevalent viral infections that can lead to sexually transmitted diseases (STD) globally [12].Out of the 200 HPVs identified, a total of 15 genotypes are known to be associated with the development of cervical cancer [13].HPV types can be further divided into high-, probably high-, and low-risk groups based on their carcinogenic properties.The high-risk group includes HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -68, -73, and -82, whereby HPV-16 and -18 cause about 70% of all invasive cervical cancers [13,14].The risk of developing cervical cancer is strongly associated with the persistence of infection, which is more commonly observed in individuals infected with high-risk oncogenic types of HPV.The primary immune response to HPV infection involves the activation of cells.Thus, individuals with conditions that weaken cell-mediated immunity, such as human immunodeficiency virus (HIV) disease or having undergone renal transplantation, have an elevated risk of acquiring and progressing HPV infection [15].Additionally, Chlamydia trachomatis infection was reported to be significantly associated with the development of cervical cancer associated with an HPV infection [16].Apart from cervical cancer, HPV infection has also been associated with a significant percentage of anogenital (anus, vulva, vagina, and penis), oral cavity, laryngeal, and head and neck cancers [17,18].Thus, HPV vaccination aimed at reducing morbidity and mortality from HPV-associated disease was introduced in 2006 and has shown high effectiveness against cervical cancer among girls vaccinated younger than 20 years old [19].

Conventional Treatment of Cervical Cancer
The type and stage of the cancer, potential side effects, the patient's preferences, and general health are all factors that influence how cervical cancer is treated.Although earlystage cervical cancer can typically be cured with surgery, chemotherapy, radiation therapy, or a combination of these treatments, advanced cervical cancer is frequently incurable and, once recurring, is generally resistant to treatment [20].
The role of minimally invasive surgery (including both laparoscopic and robotic surgery), which offers benefits such as lower operative morbidity and a shorter hospital stay compared to open surgery, like a radical hysterectomy or radical trachelectomy with pelvic lymphadenectomy, has become the standard surgical treatment for early-stage cervical cancer over the past 20 years [1].Different perspectives on cervical cancer treatment are based on the use of immunotherapy, target therapy, and poly-ADP-ribose polymerases (PARP) inhibitors alone, in combination with conventional chemotherapy, and in combination with radiotherapy [1].In 2018, pembrolizumab was a type of immune checkpoint inhibitor drug that received FDA approval for PD-L1-positive metastatic or recurrent cervical cancer [21].Currently, integrative oncology, which combines allopathic and current biological cancer treatments with complementary and alternative medicine therapies, helps in treating cervical cancer [22].
Additionally, the available therapies for cervical cancer are associated with disabling side effects and tumor drug resistance [23][24][25][26].Patients who undergo more invasive surgery, particularly, radiotherapy, report higher levels of chronic bowel, sexual, and bladder dysfunction [27,28].After the first and second cycles of concurrent chemoradiotherapy, patients under the age of 60 would substantially more frequently have symptoms of nausea and vomiting [29].This implies that having this side effect causes a "valuation shift" or higher values for adverse health states [30], as shown in Table 1.The paradigm has evolved throughout time as a result of these side effects of cancer treatment, with a greater focus currently being placed on prevention than on therapy.

Essential Oils: Composition and Their Potential Benefits
Currently, the use of EOs is focused more on the food, biomedicine, and agricultural industries.EOs extracted from medicinal plants have been reported to possess various medicinal properties, including protection from organ toxicity, acetylcholinesterase activity, and antibacterial and antioxidant properties [31][32][33].EOs consist of tens to hundreds of different chemical mixtures, such as hydrocarbons, terpenes, aldehydes, alcohols, and organic acids [34].Their composition is highly diverse across different plant species.
into alcohol, aldehydes, esters, ethers, epoxides, ketones, and phenols.Figure 1 shows the selected structure of terpenes and terpenoids.Alcohol is converted to aldehydes through a process known as dehydrogenation, which removes the hydrogen atom [57].Citral, myrtenal, benzaldehyde, and cinnamaldehyde are among the aldehydes present in EOs [44,58].Generally, aldehydes are volatile and easily oxidized.Most aldehydes are skin sensitizers and mucous membrane irritants [59].Aldehydes have pleasant fruity odors and are sweet, and they are found in culinary herbs such as cumin and cinnamon [60].Aldehydes have been reported to possess antipyretic, spasmolytic, calming, vasodilator, antiviral, tonic, and antimicrobial activities [35].
Alcoholic terpenoids are found to be spasmolytic, antiseptic, and antimicrobial [61].Examples of alcohols in EOs are linalool, borneol, nerol, citronellol, and geraniol [56].Organic acids contain the carboxyl group and are rare in EO.For example, ethanoic acid is produced in vinegar and certain aromatic waters.Acids are important to produce esters.Esters in EOs are produced during the distillation process [59].

Role of Essential Oils in Cervical Cancer: Evidence from Laboratory
In vitro and animal studies have contributed to our understanding of the potential effects of EOs on cervical cancer and the mechanisms underlying them (summarized in Table 2).According to the American National Cancer Institute, EOs that exhibit cytotoxicity with an IC50 < 30 µg/mL may be useful as anticancer agents [62].Recent studies have mostly investigated the impact of various EOs on human cervical carcinoma cell lines, Alcohol is converted to aldehydes through a process known as dehydrogenation, which removes the hydrogen atom [57].Citral, myrtenal, benzaldehyde, and cinnamaldehyde are among the aldehydes present in EOs [44,58].Generally, aldehydes are volatile and easily oxidized.Most aldehydes are skin sensitizers and mucous membrane irritants [59].Aldehydes have pleasant fruity odors and are sweet, and they are found in culinary herbs such as cumin and cinnamon [60].Aldehydes have been reported to possess antipyretic, spasmolytic, calming, vasodilator, antiviral, tonic, and antimicrobial activities [35].
Alcoholic terpenoids are found to be spasmolytic, antiseptic, and antimicrobial [61].Examples of alcohols in EOs are linalool, borneol, nerol, citronellol, and geraniol [56].Organic acids contain the carboxyl group and are rare in EO.For example, ethanoic acid is produced in vinegar and certain aromatic waters.Acids are important to produce esters.Esters in EOs are produced during the distillation process [59].
Studies suggested that EOs had inhibitory effects on cell proliferation and induced apoptosis in cancer cell lines [85,86].For example, Moirangthem et al. [87] reported that Cephalotaxus griffithii EO treatment induced cytoplasmic membrane blebbing, nuclear contraction, nuclear fragmentation, and the formation of apoptotic bodies in HeLa cells, associated with up-regulated expression of caspase-3, a central protein involved in the process of apoptosis.Similarly, Erigeron canadensis EO treatment led to increased expression of caspase-3, -9, and -12 proteins, nuclear pyknosis, and abnormal chromatin condensation in HeLa cells [88].Additionally, EOs have been shown to induce cell cycle arrest by blocking cells in the G0/G1 phase [89][90][91].
As described in the previous section, EOs contain various phytochemicals, i.e., hydrocarbons, terpenes, aldehydes, alcohols, and organic acids.As this review has shown, using EOs from the whole plant or a specific portion of the plant (e.g., leaves, stems, flowers, or roots) may prove beneficial in inhibiting cancer cell proliferation.Numerous phytochemicals found in EOs have the potential to operate singly or in combination to treat cervical cancer through a polypharmacy effect [92].However, identifying and isolating an active phytochemical should also be crucial, particularly during the drug development process.

Essential Oils Clinical Trials in Cervical Cancer and HPV Infection
Compared to the extensive studies reporting the anticancer activity of EOs in cervical cancer cells, there is a lack of comprehensive clinical data.Nevertheless, some clinical studies and trials have been conducted to investigate the potential role of EOs in cervical cancer management and the treatment of HPV infection.These studies have provided valuable insights into the efficacy and safety of EOs as a complementary therapy.Here, we summarize some key clinical findings (Table 3).No differences in regression of lesion and HPV clearance rate between intervention and control groups. [125] Blackburn et al.
[122] conducted a randomized controlled trial of 41 locally advanced cervical cancer patients who received intracavitary brachytherapy to investigate the effect of foot reflexology and aromatherapy on anxiety and pain.The results revealed a significant reduction in average pain and anxiety scores, indicating the potential benefits of foot reflexology and aromatherapy for emotional support during cancer treatment.Similarly, Sriningsih et al. [123] also reported improved chemotherapy-induced nausea and vomiting following ginger aromatherapy in post-cervical cancer chemotherapy patients.
The effect of an herbal vaginal suppository containing 10% Myrtus communis L. aqueous extract and 0.5% EO was tested in a randomized double-blind placebo trial of 60 patients with cervicovaginal HPV infection [124].Results showed that there was a significant increase in HPV test negative results and reduced cervical lesion size in the intervention group compared to the control group, suggesting that a M. communis herbal suppository can speed up virus clearance and may be effective in treating HPV infection.In contrast, topical application with a mixture of natural EOs (eugenol, carvone, nerolidol, and geraniol) in olive oil given to visual inspection of the cervix with acetic-acid-positive patients showed no differences in the regression of the lesion and HPV clearance rate between the intervention and control groups [125].

Future Directions and Challenges
The body of research on EOs in cervical cancer is continuing to grow, and ongoing research may uncover new EOs and compounds with enhanced therapeutic potential.Considering the potential benefits of EO in inhibiting cancer cell viability, further investigations are required for clinical trials.In this section, we delve into the future direction and challenges of integrating EO with conventional treatments, offering a comprehensive view of the current landscape and the path forward in cervical cancer care.

Innovation in the Delivery of Essential Oils
Although numerous studies have reported the high anticancer properties of EOs in cervical cancer cells, EOs are frequently linked to high volatility, poor stability, and being easily broken down when exposed to oxygen, heat, humidity, or light [126].Moreover, the poor solubility of EOs in water limits their bioavailability [127].Innovations in the delivery of EO, e.g., nanoparticle (NP) encapsulation, nanoemulsification, or inclusion with hydrophilic substances, may open up new avenues for the application of EOs in cancer treatment (Table 4).
The poor stability and bioavailability of EOs can be improved by encapsulating them in the form of solid lipid NPs (SLNs) [128].This technique is based on building nanostructures in which EOs are attached to or enclosed within submicron-sized capsules or NPs that enhance their bioavailability and improve targeted delivery to cancer cells [127].Eucalyptus globulus EO encapsulated to SLNs significantly enhanced the cytotoxic effect against HeLa cells, with an IC 50 of 21.30 µg/mL, compared to the EO alone (IC 50 33.20 µg/mL) [129].Similarly, encapsulation of EO's active compounds (e.g., thymoquinone, the main constituent of Nigella sativa EO, and eugenol, the main constituent of S. aromaticum EO) has been reported to have greater inhibition of HeLa cell viability compared to EOs alone [130,131].
Nanoemulsions are also recognized as an ideal vehicle for delivering lipophilic compounds due to their small particle size, simplicity in manufacture, enhanced bioavailability, biological efficacy, and kinetic stability [132].Nanoemulsifications of Rosa damascene and Melaleuca alternifolia EOs have shown great effect in inhibiting HeLa cell viability [133,134].Furthermore, M. alternifolia nanoemulsions were stable under centrifugal, freeze-thaw stress and long-term storage for up to 50 days at different temperatures [134].Combining nanoemulsions with a gel foundation forms nanoemulgels, which are particularly well suited for topical application [135].Both Coriandrum sativum and Zingiber ottensii EOs nanoemulgels have enhanced cytotoxicity to HeLa cells, compared to EO alone [136,137].However, Z. ottensii nanoemulgel (IC 50 8.88 µg/mL) reported a lower anticancer effect compared to Z. ottensii nanoemulsion (IC 50 5.81 µg/mL), most likely due to the retardation effects of the gel component of Z. ottensii nanoemulgel, which prolonged the release of Z. ottensii EO [137].
Cyclodextrins (CD) are cyclic oligosaccharides composed of (α-1,4)-glucopyrannose units, which have an unusual structure where their interior chamber is hydrophobic, and their external surface is hydrophilic.This property allows inclusion complexes to form with both inorganic and organic materials.β-CD is the most widely used CD since its cavity can hold molecules weighing between 200 and 800 g/mol [138].The β-CD/S.aromaticum inclusion complex (IC 50 12.5 µg/mL) demonstrated higher anticancer properties against HeLa cells compared to EO alone (IC 50 190.0 µg/mL) [139].However, it is important to note that the increased anticancer properties of the β-CD/S.aromaticum inclusion complex were also associated with increased cytotoxicity against normal VERO cells (IC 50 210.0µg/mL).The β-CD/Eugenia brejoensis inclusion complex increased the thermal stability of E. brejoensis EO, but also reduced the anticancer activity of E. brejoensis EO (CC 50 886.71µg/mL) when compared to EO alone (CC 50 63.20 µg/mL) [140].These results suggested that the features of the β-CD/EO inclusion complexes are influenced by the EO constituent, molecular size, and chemical structure.

Combining Essential Oils with Conventional Treatments
The integration of EO with conventional drugs in the treatment of cervical cancer aims to harness the potential synergies between the therapeutic properties of EO and current medical interventions, in order to enhance treatment efficacy.Due to its well-established anticancer, anti-inflammatory, and antioxidant properties, EO may complement the results of cancer treatment, e.g., radiation, chemotherapy, or surgery, or soothe their side effects.
Various EOs incorporated with chemotherapeutic agents showed an enhancement in cytotoxicity in cervical cancer cells.Nanoemulsions of cinnamon, peppermint, clove, lemon, salvia, chamomile, frankincense, garlic, and ginger oils loaded with chemotherapeutic agents (e.g., bleomycin, paclitaxel, ifosfamide, mitomycin C, and doxorubicin) presented a major pro-apoptotic capability in HeLa cells compared with the chemotherapeutic agents alone (Table 5) [141][142][143][144][145][146].Furthermore, peppermint-oil-based microemulsion loaded with paclitaxel was shown to be stable under centrifugal and freeze-thaw stress, and ≈90% of paclitaxel was released in the first 48 h [142].The combined therapy of monoterpenoid carvacrol-fabricated chitosan NP and doxorubicin, a topoisomerase inhibitor, has also been reported to have greater anticancer effects on HeLa cells with an IC 50 of 5.66 µg/mL, compared to doxorubicin treatment alone (IC 50 6.30µg/mL) [147].Thus, the use of EO as an adjuvant with chemotherapeutic agents can be a vital option for cancer treatment, as it will enhance the stability and efficacy of the EO.

Challenges of Using Essential Oils in Cervical Cancer Treatment
The Food and Drug Administration (FDA) has defined some EOs as Generally Recognized as Safe (GRAS) to be used as food additives [148].For example, Minthostachys verticillata EO administered on diet at doses of 0, 1, 4, and 7 g/kg feed to Wistar rats for 90 days showed no mortality, adverse effects on general conditions, or changes in body weight, food consumption, or feed conversion efficiency [149].However, there is still a lack of safety assessment studies for most EOs in animal models, as well as human studies.As the use of EOs in cervical cancer treatment evolves, it is important to address the safety of EO usage by understanding the potential adverse effects and toxicity of EOs, which are critical for patient safety.
Numerous studies have reported the potential anticancer effects of various EOs on cervical cancer cells.However, it is equally important to examine the cytotoxicity effects of these EOs on normal cells.Furthermore, as mentioned in the previous section, one of the major challenges is the lack of studies that have been performed to examine the effect of EOs on cervical cancer animal models and human patients.The shortage of these studies poses challenges in establishing the efficacy and safety of EOs for cervical cancer treatment.

Conclusions
Cervical cancer is one of the main killers of women worldwide.Various types of chemotherapeutic drugs have been developed to treat cervical cancer, but most have severe side effects on major organs such as the liver, kidney, and heart.In this review, we explore the anticancer role of various EOs, mostly in vivo against cervical cancer cells.Particularly, EOs from C. zeylanicum, C. zedoaria, F. tingitana, F. vulgare, H. italicum, L. pubescens, M. micrantha, O. acutidens, P. regnellii, R. officinalis, T. ostenii, and T. bovei have proved to exhibit superb antiproliferative effects on cervical cancer cell lines (IC 50 < 10 µg/mL).We must balance the promise of innovative research with a clear understanding of the challenges that need to be overcome for these therapies to be safe and effective in mainstream medical practice.Addressing these challenges and fostering continued research can bring us closer to realizing the full potential of EOs in cervical cancer care.

Table 1 .
Common side effects of conventional treatment for cervical cancer.

Table 2 .
Summary of essential oil in treating cervical cancer in preclinical research.

Table 3 .
Summary of essential oil in treating cervical cancer in clinical trials.

Table 4 .
Summary of essential oil in treating cervical cancer in clinical trials.

Table 5 .
Summary of essential oil in treating cervical cancer in clinical trials.