Abstract
A continuous challenge in cancer management is to improve treatment efficacy and to diminish its side effects. Consequently, new conventional and unconventional drugs and bioactive compounds from plants are constantly developed, characterized, and used for in vitro and in vivo models. This review focuses on the antitumor properties of Calendula officinalis, its biological and molecular effects in tumor cells and animal models, as well as its role in cancer palliative care. A systematic review of studies describing the cytotoxic role of C officinalis and its therapeutic role on cancer cells were carried out using the PubMed database. Albeit C officinalis extracts have cytotoxic activity toward different cancer cell lines, a high grade of variation between studies was observed, depending on plant organ subjected to extraction, extraction method, and the cancer cell lines used for each study. Nevertheless, its cytotoxic activity is related to a few bioactive compounds, presenting multiple roles in both activation of proapoptotic proteins and decreasing the expression of the proteins that inhibit cell death. Moreover, due to its anti-genotoxic/protective as well as antitumor and antimetastatic effects proven in animal models, C officinalis could have important future implications in developing novel cancer treatment strategies, while until now it has been used especially for diminishing the side effects of radiotherapy.
Introduction
Cancer ranks second among all causes of mortality worldwide, with 8.2 million cancer-related deaths in 2012. Regarding its incidence, 12 million new cases were recorded in 2012, while this number is expected to rise by about 70% over the next 2 decades.1 Depending on cancer stage, its phenotype, and localization, the ongoing treatment options include surgery, radiotherapy, chemotherapy, immunotherapy, and, when suited, hormonal therapies. If the surgery and radiotherapy are successfully used to cure solid tumors in early stages, chemotherapy represents the most important choice of cancer armamentarium for advanced cancers as well as hematological malignancies. However, these treatment options are not always efficient and have significant limitations, probably due to the high heterogeneity of tumors and the fact that the majority of cancers are identified in advanced stages. To increase the treatment efficacy and to reduce the tumor drug resistance, a combinatory regimen is currently applied.
Even if chemotherapy represents one of the most important approaches to kill cancer cells, it produces many side effects by damaging healthy tissues due to its action against all cells entering division. Therefore, both short-term and long-term cumulative cytotoxicity and several adverse effects including fatigue, hair loss, anemia, nausea and vomiting, diarrhea, constipation, mood changes, kidney problems, and dry skin are associated with adjuvant chemotherapy.2
Another major problem in cancer treatment is that tumor cells become resistant to radiochemotherapy, thus limiting the response to therapy.3 Tumor cells might become resistant either by inheriting the resistance traits from a cancerous cell subpopulation, an event known as baseline resistance and recorded in about 50% of cancer patients or by acquiring resistance over time, as a cellular response to specific drug exposure.4
If chemotherapy is considered a nontarget therapy, inducing many side effects, immunotherapy, including monoclonal antibodies, adoptive cell transfer, cytokines, and cancer vaccines, represents a reliable targeted therapy. However, it is limited to some specific tumor phenotypes. Furthermore, due to the high tumor heterogeneity and the high mutation rate, cancerous cell may acquire resistance and thus cause patient relapse.5
In this context, new conventional and unconventional anticancer drugs and compounds are constantly developed in an effort to improve cancer therapy and to diminish treatment side effects. In this regard, one of the most important research fields aiming to identify new compounds useful for cancer treatment is that related to plants.
Plants have been proved to be a relevant source of bioactive phytochemicals with cytotoxic and antitumor activity, increasing efforts being made to identify novel plant compounds as possible effective drugs in cancer treatment. Bioactive agents originating from plants like Catharanthus roseus, Podophyllum species, Taxus brevifolia, Camptotheca acuminata, Cephalotaxus species, or Curcuma longa have been long known to possess anticancer properties, with some of them being used in the treatment of different malignancies in clinical setting.6,7 Paclitaxel, a drug widely used nowadays in the treatment of different types of cancer and part of the World Health Organization’s List of Essential Medicines, represents a good example of such a compound.8 It was originally isolated from the bark of the Pacific yew, Taxus brevifolia,9 and based on its success, it has begun to be semisynthetically made under the name of Taxol/Onxol. Besides their potential of becoming part of the standard treatment in cancer, plant compounds or whole extracts are used in patient palliative care and in complementary and alternative medicine (CAM). CAM are used by around 49% of all cancer patients after the year 2000,10 herbal medicine being one of the most used types of CAM, even though many such therapies have not demonstrated their effectiveness yet.11,12
Calendula officinalis L (Asteraceae), the pot marigold, shows promising results regarding its potential use in cancer management. In this article, we review the latest updates on C officinalis anticancer activity, both in vitro and in vivo and its phytochemical constituents that present cytotoxic activity, thereby its potential usage in cancer treatment and CAM. Furthermore, we emphasize its putative role in patient’s palliative care.
Calendula officinalis in Cancer Palliative Care
Albeit C officinalis has demonstrated the cytotoxic and antitumor effects in in vitro and in vivo models, its use in human cancer management is generally limited to the treatment of the secondary effects induced by radiochemotherapy. Palliative care, an important part of cancer management nowadays, is focused on improving the quality of life in cancer patients by treating the symptoms and side effects of the disease and its treatment. With this purpose, more and more cancer patients are using CAM, including herbal remedies,10 even though little supporting scientific data are available at this moment.12 Several recent clinical trials have suggested that C officinalis extracts could be a relevant resource in diminishing the side effects of radiotherapy in breast, head, and neck cancer patients.
In a simple-blinded phase III randomized clinical trial including 254 breast cancer patients, the liposoluble fraction of C officinalis extracted in petroleum jelly was evaluated about its putative role in prevention of acute radiation-induced dermatitis of grade 2 or higher. The prevention capacity was assessed compared with trolamine, a topical agent often prescribed during radiotherapy as part of the breast cancer palliative care. The incidence of grade 2 or 3 skin acute toxicity in the Calendula-treated group was 41%, while 63% of the patients treated with trolamine showed mild to severe dermatitis. Furthermore, in the Calendula-treated group, no allergic reactions were observed and the extract proved to be more effective in reducing pain among patients. Therefore, C officinalis might be a good nonsteroid agent for the prevention of radiation-induced dermatitis in breast cancer patients.38 Albeit the effectiveness of Calendula was better than that of trolamine, it should be noted that the choice of trolamine as a reference was not based on its effectiveness in the treatment of radiotherapy-induced dermatitis, but on the data of the randomized RTOG (Radiation Therapy Oncology Group) study, which suggest its curative properties.39 Moreover, in a recent meta-analysis, trolamine was found to be ineffective in the prevention and treatment of radiation dermatitis40; thus, its usage as a control in such a clinical trial is questionable.
Another randomized, 2-armed, blinded, phase III trial was conducted on 420 patients to compare the effectiveness of 2 different commercial products: the topical Calendula cream (Weleda AG, Sweden) and an aqueous emulsion with strong moisturizing and protective qualities (Essex-Schering-Plough), in prevention of acute radiation skin reaction (ARSR) in breast cancer patients. The incidence of severe ARSR was similar in the 2 treated groups, with 23% of the patients presenting severe skin reactions for the topical Calendula cream and 19% for the aqueous cream–treated group. Therefore, the skin care product chosen had little effect on radiation-induced dermatitis.41 Overall, the patients in both groups reported lower levels of skin toxicity (23% and 19%) when compared with the patients included in the previous clinical trial (41% and 63% for the Calendula– and trolamine-treated group, respectively). The authors suggest that the decreased levels of the skin reaction symptoms are due to an improved photon therapy and a fewer smokers included in their study. Moreover, the differences between the study design and the number of patients could stand of the bottom of the differences between the data provided by these studies.
Radiodermatitis is a common side effect of radiotherapy, but it occurs more often in patients with head and neck cancer, due to the area of the treatment field. A randomized double-blind controlled clinical trial was conducted on 51 head and neck cancer patients to evaluate the effectiveness of C officinalis in the prevention and treatment of radiodermatitis in comparison with a lotion based on essential fatty acids (EFA), an often recommended palliative therapy in head and neck cancer patients. Each product was applied on the skin, twice a day, during the radiotherapy period. Calendula proved to be more effective in preventing the development of radiodermatitis, after 15 treatment sessions, the incidence of grade 1 dermatitis being 40.73% for the EFA group and only 25% in the Calendula-treated group. Furthermore, after the last session of radiotherapy, the incidence of grade 2 or 3 radiodermatitis was 21.43% for the Calendula-treated group, while in the EFA group, it was almost double (46.16%). Although Calendula proved to be a better palliative care option than EFA treatment for the prevention of radiation-induced dermatitis in head and neck cancer patients, it has to be mentioned that only 27 patients were finally included for statistical analysis.42 Furthermore, even though EFA lotions are an often recommended palliative therapy in some clinics,42 there are no available studies in the literature that prove their effectiveness in the prevention of radiation-induced skin toxicity.
Another relevant side effect of radiotherapy in head and neck patients is the radiation-induced oropharyngeal mucositis (OM), with more than 80% of the patients reporting an inflammation of the oral mucosa during treatment.43 In this context, a placebo-controlled clinical trial conducted on 40 head and neck cancer patients proved that C officinalis flower extract mouthwash significantly decreased the intensity of radiation-induced OM after 2, 3, and 6 weeks of treatment. The authors suggest that the inhibition of OM occurrence is at least partially caused by the extract antioxidant capacity.44
Using different referent agents, such as hyaluronic acid Aloe vera, corticosteroid cream, commercial emulsion with strong moisturizing and protective qualities, or placebo, makes the data difficult to compare between studies. Moreover, different kinds of study designs including simple- or double-blind randomized studies may introduce sources of bias in treatment assignments. Generally, the studies have partially described the biases risks and how they could be avoided. In a previous study, it was highlighted that trials with inadequate or unclear randomization design lead to overestimation of the treatment effects up to 40% compared with data from trials with proper randomization.45
However, even if data from previous studies are not really comparable, it is already stated that Calendula could be considered for human cancer management, especially for the treatment of the secondary effects induced by radiochemotherapy. Further studies based on proper randomization design and using high number of patients will certainly establish the efficiency and usefulness of Calendula in cancer management.
Conclusions, Challenges, and Perspectives
Calendula officinalis extracts and isolated compounds have revealed a reliable potential in cancer management, both in treatment and in palliative care. Several extracts present significant in vitro selective cytotoxicity toward large panels of cancer cell lines when compared with healthy cells. The cytotoxic activity against cancer cell lines reported for different C officinalis extracts varies widely among recent studies (IC50 values between 50.5 and 2300 µg/mL). Most of the recent research was conducted on flowers/flos extracts, even though Wegiera et al33 suggested that root extracts might possess higher cytotoxicity toward cancer cell lines. Accordingly, even if no study presented data on a combination of flower and roots extracts, we consider that this approach could represent a challenge that has to be explored in the near future. Methanol is the most used solvent for extraction. Extracts obtained through infusion in distilled water have lower cytotoxic activities, even though Jimenez-Medina et al31 reported much better results if the aqueous extract is laser-activated. Nevertheless, the methanolic extract of C officinalis flowers did not have selective cytotoxicity toward cancer cell lines when compared with HSFs, while the ethyl acetate extract selectively killed tumor cells in the same experimental design.29 The aqueous extract obtained from flowers also proved to possess selective cytotoxic activity against different cancer cell lines when compared with healthy PBMCs.30 Furthermore, the laser-activated aqueous extract proved to have immunostimulant activity, by increasing the proliferation of several PBL subpopulations.31 As a consequence, different extraction procedures that use distilled water as the extraction solvent might be better options than extraction in methanol, even though the cytotoxic activity against cancer cell lines is lower for the aqueous extracts.
However, all the IC50 values reported for the C officinalis extracts are rather high, none of them being smaller than 20 µg/mL, the standard threshold concentration used in conventional drug discovery studies, according to the US National Cancer Institute.46 In this context, the required dose for effective cytotoxicity in vivo, based on the in vitro results, would be most probably higher than the safe dose. Furthermore, achieving in vivo plasma concentration higher than 20 µg/mL for extracts is difficult, leading to limitations in the uptake of the active compounds.47 Therefore, the chances that singular extracts from C officinalis to be used as a treatment option in clinical settings are greatly diminished. However, the required doses for effective cytotoxicity in vivo might be decreased by using synergistic combinations with other plant formulas, a highly recommended approach for drugs isolated from plants.47 Further in vitro investigations are needed to assess the synergistic effect of C officinalis extracts with other known anticancer plant compounds.
C officinalis extracts proved to have no or low general toxicity in animal models, while they possessed chemopreventive, antitumor, and antimetastatic activity in vivo. Research conducted to date has emphasized different C officinalis extracts without in vivo toxicity when used for oral administration from 1 to 5 g/kg body weight in mice and rat models, respectively,34 or up to 55 mg/kg body weight in mice and 550 mg/kg in rats.31 Nevertheless, the posttreatment possibility of hepatic and renal overload was suggested.34 Both aqueous-ethanol35 and methanol36 extracts of C officinalis flowers proved to have chemopreventive/anti-genotoxic activities in 2 different carcinogenesis models, at much lower effective concentrations than the toxicity threshold concentration identified in all other studies.29,32 However, Barajas-Farias et al suggest that the extract not only becomes genotoxic if administrated in high doses but also could replace the carcinogenesis promoter. The in vivo antitumor cytotoxic activity was proven in nude mice bearing ANDO-2 human melanoma cell line, in which the LACE extract inhibited the tumor growth by 60% and significantly extended the animal’s life span.31 Moreover, another C officinalis flowers extract increased the life span by 43% in lab mice injected with B16F-10 melanoma cells and possessed antimetastatic activity in these tumor-bearing mice.
Only 3 compounds were individually identified in C officinalis extracts to possess cytotoxic activity against different cancer cell lines. However, there is a high possibility for other constituents, mainly terpenoids and polyphenols, to be further identified as antitumor agents. Lutein was found to have selective cytotoxicity toward breast cancer cell lines, by inducing apoptosis in these cells.27 Other 2 triterpene glycosides were identified as highly cytotoxic against a large panel of cancer cell lines in vitro.28 According to the US National Cancer Institute plant screening program, for a compound to be considered cytotoxic toward cancer cell lines, the IC50 values have to be <10 µM.46 Therefore, at least the calenduloside F 6’-O–n-butyl ester compound shows promising results as a potential anticancer drug.
Finally, C officinalis extracts might be good alternatives to current palliative treatments, which aim to diminish the side effects of radiotherapy. Two phase III randomized clinical trials, totalizing 674 breast cancer patients, tested the effectiveness of Calendula extracts in the prevention of acute radiation-induced dermatitis.38,41 In the first one, the extract proved to be superior in its activity when compared with trolamine.38 However, in a recent study, trolamine proved to be ineffective in the prevention of radiotherapy-associated dermatitis.40 In the second clinical trial, Sharp et al41 found no differences in the prevention of ARSR when comparing the standard Calendula cream and a topical aqueous cream often prescribed during radiation treatment. None of these studies use a vehicle-controlled placebo; thus, the effectiveness of the Calendula-based treatments is not actually assessed. Taking into consideration these conflicting data and the absence of the placebo groups from the studies, Calendula products might be good alternatives to the topical palliative treatments of radiation-induced dermatitis in breast cancer patients, but further investigations regarding their efficacy are necessary.
Two other clinical trials suggest that different C officinalis extracts are effective in the prevention and treatment of radiodermatitis42 and of radiation-induced OM44 in head and neck cancer patients. The first extract showed better results in preventing dermatitis than the EFA treatment.42 However, there are no data available at this moment to prove the effectiveness of EFA lotions in preventing radiation-induced OM. Furthermore, no placebo group was used in this clinical trial; thus, issues regarding the actual effectiveness of the Calendula extract are raised again.
In conclusion, Calendula officinalis shows promising results regarding its potential usage in cancer management, especially in cancer prevention, treatment, and in palliative care. However, without knowing the bioactive constituents responsible for the in vitro and in vivo selective cytotoxicity as well as for the prevention of radiotherapy-induced side effects, moving forward to relevant preclinical trials is hampered. Therefore, intensive research is essential toward identifying novel C officinalis constituents, which might become relevant resources in cancer management.
- Daniel Cruceriu
- https://drive.google.com/drive/folders/1NYK03M1V86ZyMs8j1loZ67IVgTS64a-y?usp=sharing
- https://journals.sagepub.com/doi/10.1177/1534735418803766
- The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
Add Comment