In vitro activities and mechanisms of action of anti-cancer molecules from African medicinal plants: a systematic review.

Cancer is one of the leading causes of death worldwide. In recent years, African countries have been faced with a rapid increase in morbidity and mortality due to this pathology. Management is often complicated by the high treatment costs, side effects and the increasing occurrence of resistance to treatments. The identification of new active ingredients extracted from endemic medicinal plants is definitively an interesting approach for the implementation of new therapeutic strategies: their extraction is often lower cost; their identification is based on an ethnobotanical history and a tradipratic approach; their use by low-income populations is simpler; this can help in the development of new synthetic molecules that are more active, more effective and with fewer side effects. The objective of this review is to document the molecules derived from African medicinal plants whose in vitro anti-cancer activities and the mechanisms of molecular actions have been identified. From the scientific databases Science Direct, PubMed and Google Scholar, we searched for publications on compounds isolated from African medicinal plants and having activity on cancer cells in culture. The data were analyzed in particular with regard to the cytotoxicity of the compounds and their mode of action. A total of 90 compounds of these African medicinal plants were selected. They come from nine chemical groups: alkaloids, flavonoids, polyphenols, quinones, saponins, steroids, terpenoids, xanthones and organic sulfides. These compounds have been associated with several cellular effects: i) Cytotoxicity, including caspase activation, alteration of mitochondrial membrane potential, and/or induction of reactive oxygen species (ROS); ii) Anti-angiogenesis; iii) Anti-metastatic properties. This review points out that the cited African plants are rich in active ingredients with anticancer properties. It also stresses that screening of these anti-tumor active ingredients should be continued at the continental scale. Altogether, this work provides a rational basis for the selection of phytochemical compounds for use in clinical trials.

Contribution of Sub-Saharan African medicinal plants to cancer research: Scientific basis 2013-2023.

Cancer incidence and mortality rates are increasing worldwide. Cancer treatment remains a real challenge for African countries, especially in sub-Saharan Africa where funding and resources are very limited. High costs, side effects and drug resistance associated with cancer treatment have encouraged scientists to invest in research into new herbal cancer drugs. In order to identify potential anticancer plants for drug development, this review aims to collect and summarize anticancer activities (in vitro/in vivo) and molecular mechanisms of sub-Saharan African medicinal plant extracts against cancer cell lines. Scientific databases such as ScienceDirect, Google Scholar and PubMed were used to search for research articles published from January 2013 to May 2023 on anticancer medicinal plants in sub-Saharan Africa. The data were analyzed to highlight the cytotoxicity and molecular mechanisms of action of these listed plants. A total of 85 research papers covering 204 medicinal plant species were selected for this review. These plants come from 57 families, the most dominant being the plants of the family Amaryllidaceae (16), Fabaceae (14), Annonaceae (10), Asteraceae (10). Plant extracts exert their anticancer activity mainly by inducing apoptosis and stopping the cell cycle of cancer cells. Several plant extracts from sub-Saharan Africa therefore have strong potential for the search for original anticancer phytochemicals. Chemoproteomics, multi-omics, genetic editing technology (CRISPR/Cas9), combined therapies and artificial intelligence tools are cutting edge emerging technologies that facilitate the discovery and structural understanding of anticancer molecules of medicinal plants, reveal their direct targets, explore their therapeutic uses and molecular bases.

Chemical Composition of Essential Oil of Cymbopogon schoenanthus (L.) Spreng from Burkina Faso, and Effects against Prostate and Cervical Cancer Cell Lines.

The aim of this research was to evaluate the essential oil of Cymbopogon schoenanthus (L.) Spreng. (C. schoenanthus) from Burkina Faso in terms of cytotoxic activity against LNCaP cells, derived from prostate cancer, and HeLa cells, derived from cervical cancer. Antioxidant activities were evaluated in vitro. Essential oil (EO) was extracted by hydrodistillation and analyzed by GC/FID and GC/MS. Thirty-seven compounds were identified, the major compounds being piperitone (49.9%), δ-2-carene (24.02%), elemol (5.79%) and limonene (4.31%). EO exhibited a poor antioxidant activity, as shown by the inhibition of DPPH radicals (IC50 = 1730 ± 80 µg/mL) and ABTS+. (IC50 = 2890 ± 26.9 µg/mL). Conversely, EO decreased the proliferation of LNCaP and HeLa cells with respective IC50 values of 135.53 ± 5.27 µg/mL and 146.17 ± 11 µg/mL. EO also prevented LNCaP cell migration and led to the arrest of their cell cycle in the G2/M phase. Altogether, this work points out for the first time that EO of C. schoenanthus from Burkina Faso could be an effective natural anticancer agent.

Harnessing the reverse cholesterol transport pathway to favor differentiation of monocyte-derived APCs and antitumor responses.

Lipid and cholesterol metabolism play a crucial role in tumor cell behavior and in shaping the tumor microenvironment. In particular, enzymatic and non-enzymatic cholesterol metabolism, and derived metabolites control dendritic cell (DC) functions, ultimately impacting tumor antigen presentation within and outside the tumor mass, dampening tumor immunity and immunotherapeutic attempts. The mechanisms accounting for such events remain largely to be defined. Here we perturbed (oxy)sterol metabolism genetically and pharmacologically and analyzed the tumor lipidome landscape in relation to the tumor-infiltrating immune cells. We report that perturbing the lipidome of tumor microenvironment by the expression of sulfotransferase 2B1b crucial in cholesterol and oxysterol sulfate synthesis, favored intratumoral representation of monocyte-derived antigen-presenting cells, including monocyte-DCs. We also found that treating mice with a newly developed antagonist of the oxysterol receptors Liver X Receptors (LXRs), promoted intratumoral monocyte-DC differentiation, delayed tumor growth and synergized with anti-PD-1 immunotherapy and adoptive T cell therapy. Of note, looking at LXR/cholesterol gene signature in melanoma patients treated with anti-PD-1-based immunotherapy predicted diverse clinical outcomes. Indeed, patients whose tumors were poorly infiltrated by monocytes/macrophages expressing LXR target genes showed improved survival over the course of therapy. Thus, our data support a role for (oxy)sterol metabolism in shaping monocyte-to-DC differentiation, and in tumor antigen presentation critical for responsiveness to immunotherapy. The identification of a new LXR antagonist opens new treatment avenues for cancer patients.

Screening for liver X receptor modulators: Where are we and for what use?

Liver X receptors (LXRs) are members of the nuclear receptor superfamily that are canonically activated by oxidized derivatives of cholesterol. Since the mid-90s, numerous groups have identified LXRs as endocrine receptors that are involved in the regulation of various physiological functions. As a result, when their expression is genetically modified in mice, phenotypic analyses reveal endocrine disorders ranging from infertility to diabetes and obesity, nervous system pathologies such Alzheimer's or Parkinson's disease, immunological disturbances, inflammatory response, and enhancement of tumour development. Based on such findings, it appears that LXRs could constitute good pharmacological targets to prevent and/or to treat these diseases. This review discusses the various aspects of LXR drug discovery, from the tools available for the screening of potential LXR modulators to the current situational analysis of the drugs in development. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Absence of nuclear receptors LXRs impairs immune response to androgen deprivation and leads to prostate neoplasia.

Chronic inflammation is now a well-known precursor for cancer development. Infectious prostatitis are the most common causes of prostate inflammation, but emerging evidence points the role of metabolic disorders as a potential source of cancer-related inflammation. Although the widely used treatment for prostate cancer based on androgen deprivation therapy (ADT) effectively decreases tumor size, it also causes profound alterations in immune tumor microenvironment within the prostate. Here, we demonstrate that prostates of a mouse model invalidated for nuclear receptors liver X receptors (LXRs), crucial lipid metabolism and inflammation integrators, respond in an unexpected way to androgen deprivation. Indeed, we observed profound alterations in immune cells composition, which was associated with chronic inflammation of the prostate. This was explained by the recruitment of phagocytosis-deficient macrophages leading to aberrant hyporesponse to castration. This phenotypic alteration was sufficient to allow prostatic neoplasia. Altogether, these data suggest that ADT and inflammation resulting from metabolic alterations interact to promote aberrant proliferation of epithelial prostate cells and development of neoplasia. This raises the question of the benefit of ADT for patients with metabolic disorders.

Effects of extracts and molecules derived from medicinal plants of West Africa in the prevention and treatment of gynecological cancers. A Review.

Medicinal plants are a potential source of drug discovery and development of new pharmacological compounds for cancer chemoprevention. More than 80% of the West African population uses medicinal plants. It is estimated that over 60% of approved anti-cancer agents are derived from plants. The plant raw material used in African traditional medicine and particularly in West Africa can be an important source for the research of anti-tumor drugs against gynecological cancers. These tumors have a negative impact on women's general health status and causes enormous health costs as they affect all age groups. Gynecological cancers remain thus a major concern worldwide, especially in West Africa where these cancers are the leading cause of cancer deaths in women. This review reports on the contribution of West African flora to the discovery of potential antiproliferative and/or cytotoxic phytochemical compounds against gynecological cancer cells. Scientific databases such as PubMed, ScienceDirect, Scopus and GoogleScholar were used to extract publications reporting West African plants and/or isolated compounds used in cell models of gynecological cancers. Thresholds of cytotoxicity and modes of action of these phytochemicals have been summarized. This research can serve as a basis for taking medicinal plants into account in the management of these gynecological cancers in resource-limited countries such as those in West Africa.

Pharmacological Modulation of Steroid Activity in Hormone-Dependent Breast and Prostate Cancers: Effect of Some Plant Extract Derivatives.

: The great majority of breast and prostate tumors are hormone-dependent cancers; hence, estrogens and androgens can, respectively, drive their developments, making it possible to use pharmacological therapies in their hormone-dependent phases by targeting the levels of steroid or modulating their physiological activity through their respective nuclear receptors when the tumors relapse. Unfortunately, at some stage, both breast and prostate cancers become resistant to pharmacological treatments that aim to block their receptors, estrogen (ER) or androgen (AR) receptors, respectively. So far, antiestrogens and antiandrogens used in clinics have been designed based on their structural analogies with natural hormones, 17-ß estradiol and dihydrotestosterone. Plants are a potential source of drug discovery and the development of new pharmacological compounds. The aim of this review article is to highlight the recent advances in the pharmacological modulation of androgen or estrogen levels, and their activity through their cognate nuclear receptors in prostate or breast cancer and the effects of some plants extracts.

Sequential Ras/MAPK and PI3K/AKT/mTOR pathways recruitment drives basal extrusion in the prostate-like gland of Drosophila.

One of the most important but less understood step of epithelial tumourigenesis occurs when cells acquire the ability to leave their epithelial compartment. This phenomenon, described as basal epithelial cell extrusion (basal extrusion), represents the first step of tumour invasion. However, due to lack of adequate in vivo model, implication of emblematic signalling pathways such as Ras/Mitogen-Activated Protein Kinase (MAPK) and phosphoinositide 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathways, is scarcely described in this phenomenon. We have developed a unique model of basal extrusion in the Drosophila accessory gland. There, we demonstrate that both Ras/MAPK and PI3K/AKT/mTOR pathways are necessary for basal extrusion. Furthermore, as in prostate cancer, we show that these pathways are co-activated. This occurs through set up of Epidermal Growth Factor Receptor (EGFR) and Insulin Receptor (InR) dependent autocrine loops, a phenomenon that, considering human data, could be relevant for prostate cancer.

Chemical composition, antioxidant, anti-inflammatory and antiproliferative activities of the essential oil of Cymbopogon nardus, a plant used in traditional medicine.

Objectives Natural products commonly used in traditional medicine, such as essential oils (EOs), are attractive sources for the development of molecules with anti-proliferative activities for future treatment of human cancers, e.g., prostate and cervical cancer. In this study, the chemical composition of the EO from Cymbopogon nardus was characterized, as well as its antioxidativeproperties and anti-inflammatory and antiproliferative activities on LNCaP cells derived from prostate cancer. Methods The chemical composition of the EO was determined by GC/FID and GC/MS analyses. The antioxidative properties were assessed using DPPH radical scavenging assay and ABTS+• radical cation decolorization assay, and the anti-inflammatory capacity was determined by the inhibition of the lipoxygenase activity. Antiproliferative activity was evaluated by MTT assay. Results Collectively, our data show that the major constituents of C. nardus EO are citronellal (33.06 %), geraniol (28.40 %), nerol (10.94 %), elemol (5.25 %) and delta-elemene (4.09 %). C. nardus EO shows modest antioxidant and anti-inflammatory activity compared to the standard galic acid. C. nardus EO exhibits the best antiproliferative activity on the prostate cancer cell line LNCaP with an IC50 of 58.0 ± 7.9 µg/mL, acting through the induction of the cell cycle arrest. Conclusions This study has determined that C. nardus EO efficiently triggers cytotoxicity and pens a new field of investigation regarding the putative use of this EO in vivo.

Flavonoids differentially modulate liver X receptors activity-Structure-function relationship analysis.

Liver X receptors (LXRs) α (NR1H3) and ß (NR1H2) are nuclear receptors that have been involved in the regulation of many physiological processes, principally in the control of cholesterol homeostasis, as well as in the control of the cell death and proliferation balance. These receptors are thus promising therapeutic targets in various pathologies such as dyslipidemia, atherosclerosis, diabetes and/or cancers. These receptors are known to be activated by specific oxysterol compounds. The screening for LXR-specific ligands is a challenging process: indeed, these molecules should present a specificity towards each LXR-isoform. Because some natural products have significant effects in the regulation of the LXR-regulated homeostasis and are enriched in flavonoids, we have decided to test in cell culture the effects of 4 selected flavonoids (galangin, quercetin, apigenin and naringenin) on the modulation of LXR activity using double-hybrid experiments. In silico, molecular docking suggests specific binding pattern between agonistic and antagonistic molecules. Altogether, these results allow a better understanding of the ligand binding pocket of LXRα/ß. They also improve our knowledge about flavonoid mechanism of action, allowing the selection and development of better LXR selective ligands.

Ethanolic extract of Algerian propolis decreases androgen receptor transcriptional activity in cultured LNCaP cells.

Antiandrogens have a peculiar place in the treatment of metastatic prostate cancer by blocking the androgen receptor (AR). Unfortunately, aggressive tumors could rapidly develop into a castration resistant state. It is therefore essential to look for new molecules that are more effective, affecting not only the androgen signaling and with minimum undesirable effects. Natural products are an interesting source of new therapeutics, especially for cancer therapy as 70% of them have botanical origin. Based on an ethnobotany screening, we evaluated the effects of ethanolic extract of propolis (EEP) from Algeria on LNCaP cells. Results pointed out that EEP reduces the survival of LNCaP cells with an IC50 of 0.04 mg/ml, induces the apoptosis and blocks the cell cycle at G0/G1 phase. Interestingly, EEP decreased the accumulation of AR suggesting some anti-androgen activity. Indeed, secreted amount of the androgen target protein PSA was decreased when LNCaP cells were incubated with EEP, starting after 4 h of treatment. This anti-androgen activity was also shown on the androgen target genes Fkbp5 and Sgk1. Finally, the capacity of EEP to block AR functioning was demonstrated in transient transfections with human AR and the reporter gene ARE-tk-Luc. Propolis antagonizes the induction of the luciferase activity induced by the natural androgen DHT (10-8M) or the synthetic AR agonist R1881 (10-7M). Altogether, these results highlight the potential pharmacological effects of EEP in future treatments of prostate cancer.

Stress as an immunomodulator: liver X receptors maybe the answer.

Stress is a reflex response, both psychological and physiological, of the body to a difficult situation that requires adaptation. Stress is at the intersection of the objective event and the subjective event. The physiological mechanisms involved in chronic stress are numerous and can contribute to a wide variety of disorders, in all systems including the immune system. Stress modifies the Th1/Th2 balance via the HPA axis and a set of immune mediators. This will make the body more vulnerable to external infections in a scientific way while others claim the opposite, stress could be considered immune stimulatory. The development of synthetic LXR ligands such as T0901317 and GW3965 as well as an understanding of the direct involvement of these receptors in the regulation of proopiomelanocortin (POMC) gene expression and indirectly by producing a variety of cytokines in a stressor response, will open in the near future new therapeutic methods against the undesirable effects of stress on the behavior of the immune system.

New Insights in Prostate Cancer Development and Tumor Therapy: Modulation of Nuclear Receptors and the Specific Role of Liver X Receptors.

Prostate cancer (PCa) incidence has been dramatically increasing these last years in westernized countries. Though localized PCa is usually treated by radical prostatectomy, androgen deprivation therapy is preferred in locally advanced disease in combination with chemotherapy. Unfortunately, PCa goes into a castration-resistant state in the vast majority of the cases, leading to questions about the molecular mechanisms involving the steroids and their respective nuclear receptors in this relapse. Interestingly, liver X receptors (LXRα/NR1H3 and LXRß/NR1H2) have emerged as new actors in prostate physiology, beyond their historical roles of cholesterol sensors. More importantly LXRs have been proposed to be good pharmacological targets in PCa. This rational has been based on numerous experiments performed in PCa cell lines and genetic animal models pointing out that using selective liver X receptor modulators (SLiMs) could actually be a good complementary therapy in patients with a castration resistant PCa. Hence, this review is focused on the interaction among the androgen receptors (AR/NR3C4), estrogen receptors (ERα/NR3A1 and ERß/NR3A2), and LXRs in prostate homeostasis and their putative pharmacological modulations in parallel to the patients' support.

Cholesterol: A Gatekeeper of Male Fertility?

Cholesterol is essential for mammalian cell functions and integrity. It is an important structural component maintaining the permeability and fluidity of the cell membrane. The balance between synthesis and catabolism of cholesterol should be tightly regulated to ensure normal cellular processes. Male reproductive function has been demonstrated to be dependent on cholesterol homeostasis. Here we review data highlighting the impacts of cholesterol homeostasis on male fertility and the molecular mechanisms implicated through the signaling pathways of some nuclear receptors.

Liver X Receptors: A Possible Link between Lipid Disorders and Female Infertility.

A close relationship exists between cholesterol and female reproductive physiology. Indeed, cholesterol is crucial for steroid synthesis by ovary and placenta, and primordial for cell structure during folliculogenesis. Furthermore, oxysterols, cholesterol-derived ligands, play a potential role in oocyte maturation. Anomalies of cholesterol metabolism are frequently linked to infertility. However, little is known about the molecular mechanisms. In parallel, increasing evidence describing the biological roles of liver X receptors (LXRs) in the regulation of steroid synthesis and inflammation, two processes necessary for follicle maturation and ovulation. Both of the isoforms of LXRs and their bona fide ligands are present in the ovary. LXR-deficient mice develop late sterility due to abnormal oocyte maturation and increased oocyte atresia. These mice also have an ovarian hyper stimulation syndrome in response to gonadotropin stimulation. Hence, further studies are necessary to explore their specific roles in oocyte, granulosa, and theca cells. LXRs also modulate estrogen signaling and this could explain the putative protective role of the LXRs in breast cancer growth. Altogether, clinical studies would be important for determining the physiological relevance of LXRs in reproductive disorders in women.

Retraction Note: Liver X receptors constrain tumor development and metastasis dissemination in PTEN-deficient prostate cancer.

This paper has been retracted at the request of the authors.

Cymbopogon citratus and Cymbopogon giganteus essential oils have cytotoxic effects on tumor cell cultures. Identification of citral as a new putative anti-proliferative molecule.

Cymbopogon species are used as traditional remedies in Burkina Faso for treating several diseases. We aimed to study the effects of their essential oils on cancer cell lines. For that purpose, Cymbopogon citratus (DC.) Stapf. and Cymbopogon giganteus Chiov. were studied for their essential oils after various chemical extractions. Antioxidant, potential anti-inflammatory action (inhibition of lipoxygenase) and cytotoxic activities were also tested on various prostate cancer and glioblastoma cell lines. Thirty-three compounds were identified in the essential oil of C. giganteus: Limonene (19.33%), Mentha-1(7),8-dien-2-ol cis (17.34%), Mentha-1(7),8-dien-2-ol trans (13.95%), trans-Mentha-2,8-diene-para-ol 1 (13.91%) and Mentha-2,8-diene-1-ol, cis-para (8.10%) were the most abundant. C. citratus essential oil contained 15 compounds and the major ones were geranial/citral A (48.18%) and neral/citral B (34.37%). Essential oil of C. citratus showed the highest ability to scavenge DPPH+ radicals (approximately 68% at 8 mg/mL) while C. giganteus exhibited the highest capability to reduce ABTS+ (0.59µmolET/g). The essential oil of C. citratus was the most effective on prostate cell lines LNCaP (IC50 = 6.36 µg/ml) and PC-3 (IC50 = 32.1 µg/ml), and on glioblastoma cell lines (SF-767 (IC50 = 45.13 µg/ml) and SF-763 (IC50 = 172.05 µg/ml). Interestingly, the activity of essential oil of C. citratus was statistically equal to that of its major component, citral. Combination of both oils showed antagonist, additive, indifferent and synergistic effects on LNCaP, PC-3, SF-767 and SF-763 cell lines, respectively. In conclusion, plants from the traditional medicine in Burkina Faso could be of interest for identifying new compounds, such as citral, for the treatment of prostate cancer and glioblastoma.

Liver X Receptor Genes Variants Modulate ALS Phenotype.

Amyotrophic lateral sclerosis (ALS) is one of the most severe motor neuron (MN) disorders in adults. Phenotype of ALS patients is highly variable and may be influenced by modulators of energy metabolism. Recent works have implicated the liver X receptors α and ß (LXRs), either in the propagation process of ALS or in the maintenance of MN survival. LXRs are nuclear receptors activated by oxysterols, modulating cholesterol levels, a suspected modulator of ALS severity. In a cohort of 438 ALS patients and 330 healthy controls, the influence of LXR genes on ALS risk and phenotype was studied using single nucleotide polymorphisms (SNPs). The two LXRα SNPs rs2279238 and rs7120118 were shown to be associated with age at onset in ALS patients. Consistently, homozygotes were twice more correlated than were heterozygotes to delayed onset. The onset was thus delayed by 3.9 years for rs2279238 C/T carriers and 7.8 years for T/T carriers. Similar results were obtained for rs7120118 (+2.1 years and +6.7 years for T/C and C/C genotypes, respectively). The LXRß SNP rs2695121 was also shown to be associated with a 30% increase of ALS duration (p = 0.0055, FDR = 0.044). The tested genotypes were not associated with ALS risk. These findings add further evidence to the suspected implication of LXR genes in the disease process of ALS and might open new perspectives in ALS therapeutics.