Cameroonian Medicinal Plants: Pharmacology and Derived Natural Products

Many developing countries including Cameroon have mortality patterns that reflect high levels of infectious diseases and the risk of death during pregnancy and childbirth, in addition to cancers, cardiovascular diseases and chronic respiratory diseases that account for most deaths in the developed world. Several medicinal plants are used traditionally for their treatment. In this review, plants used in Cameroonian traditional medicine with evidence for the activities of their crude extracts and/or derived products have been discussed. A considerable number of plant extracts and isolated compounds possess significant antimicrobial, anti-parasitic including antimalarial, anti-proliferative, anti-inflammatory, anti-diabetes, and antioxidant effects. Most of the biologically active compounds belong to terpenoids, phenolics, and alkaloids. Terpenoids from Cameroonian plants showed best activities as anti-parasitic, but rather poor antimicrobial effects. The best antimicrobial, anti-proliferative, and antioxidant compounds were phenolics. In conclusion, many medicinal plants traditionally used in Cameroon to treat various ailments displayed good activities in vitro. This explains the endeavor of Cameroonian research institutes in drug discovery from indigenous medicinal plants. However, much work is still to be done to standardize methodologies and to study the mechanisms of action of isolated natural products

A Randomised, Double Blind, Placebo-Controlled Pilot Study of Oral Artesunate Therapy for Colorectal Cancer.

BACKGROUND: Artesunate is an antimalarial agent with broad anti-cancer activity in in vitro and animal experiments and case reports. Artesunate has not been studied in rigorous clinical trials for anticancer effects. AIM: To determine the anticancer effect and tolerability of oral artesunate in colorectal cancer (CRC). METHODS: This was a single centre, randomised, double-blind, placebo-controlled trial. Patients planned for curative resection of biopsy confirmed single primary site CRC were randomised (n = 23) by computer-generated code supplied in opaque envelopes to receive preoperatively either 14 daily doses of oral artesunate (200 mg; n = 12) or placebo (n = 11). The primary outcome measure was the proportion of tumour cells undergoing apoptosis (significant if > 7% showed Tunel staining). Secondary immunohistochemical outcomes assessed these tumour markers: VEGF, EGFR, c-MYC, CD31, Ki67 and p53, and clinical responses. FINDINGS: 20 patients (artesunate = 9, placebo = 11) completed the trial per protocol. Randomization groups were comparable clinically and for tumour characteristics. Apoptosis in > 7% of cells was seen in 67% and 55% of patients in artesunate and placebo groups, respectively. Using Bayesian analysis, the probabilities of an artesunate treatment effect reducing Ki67 and increasing CD31 expression were 0.89 and 0.79, respectively. During a median follow up of 42 months 1 patient in the artesunate and 6 patients in the placebo group developed recurrent CRC. INTERPRETATION: Artesunate has anti-proliferative properties in CRC and is generally well tolerated

Three-Dimensional Modeling of Glucose-6-phosphate Dehydrogenase-Deficient Variants from German Ancestry

Loss of function of dimeric glucose-6-phosphate dehydrogenase (G6PD) represents the most common inborn error of metabolism throughout the world affecting an estimated 400 million people. In Germany, this enzymopathy is very rare. units. Three mutations, i.e. G6PD Munich, G6PD Riverside and G6PD Gastonia, lie closer to the interface of the two monomers. These may also affect the interface of two monomers.None of these G6PD variants share mutations with the common G6PD variants known from the Mediterranean, Near East, or Africa indicating that they have developed independently. The G6PD variants have been compared with mutants from other populations and the implications for survival of G6PD variants from natural selection have been discussed

Role of Transferrin Receptor and the ABC Transporters ABCB6 and ABCB7 for Resistance and Differentiation of Tumor Cells towards Artesunate

The anti-malarial artesunate also exerts profound anti-cancer activity. The susceptibility of tumor cells to artesunate can be enhanced by ferrous iron. The transferrin receptor (TfR) is involved in iron uptake by internalization of transferrin and is over-expressed in rapidly growing tumors. The ATP-binding cassette (ABC) transporters ABCB6 and ABCB7 are also involved in iron homeostasis. To investigate whether these proteins play a role for sensitivity towards artesunate, Oncotest's 36 cell line panel was treated with artesunate or artesunate plus iron(II) glycine sulfate (Ferrosanol®). The majority of cell lines showed increased inhibition rates, for the combination of artesunate plus iron(II) glycine sulfate compared to artesunate alone. However, in 11 out of the 36 cell lines the combination treatment was not superior. Cell lines with high TfR expression significantly correlated with high degrees of modulation indicating that high TfR expressing tumor cells would be more efficiently inhibited by this combination treatment than low TfR expressing ones. Furthermore, we found a significant relationship between cellular response to artesunate and TfR expression in 55 cell lines of the National Cancer Institute (NCI), USA. A significant correlation was also found for ABCB6, but not for ABCB7 in the NCI panel. Artesunate treatment of human CCRF-CEM leukemia and MCF7 breast cancer cells induced ABCB6 expression but repressed ABCB7 expression. Finally, artesunate inhibited proliferation and differentiation of mouse erythroleukemia (MEL) cells. Down-regulation of ABCB6 by antisense oligonucleotides inhibited differentiation of MEL cells indicating that artesunate and ABCB6 may cooperate. In conclusion, our results indicate that ferrous iron improves the activity of artesunate in some but not all tumor cell lines. Several factors involved in iron homeostasis such as TfR and ABCB6 may contribute to this effect

Artesunate induces oncosis-like cell death in vitro and has antitumor activity against pancreatic cancer xenografts in vivo

Pancreatic cancer is highly resistant to the currently available chemotherapeutic agents. Less than 5% of patients diagnosed with this disease could survive beyond 5 years. Thus, there is an urgent need for the development of novel, efficacious drugs that can treat pancreatic cancer. Herein we report the identification of artesunate (ART), a derivative of artemisinin, as a potent and selective antitumor agent against human pancreatic cancer cells in vitro and in vivo. ART exhibits selective cytotoxic activity against Panc-1, BxPC-3 and CFPAC-1 pancreatic cancer cells with IC50 values that are 2.3- to 24-fold less than that of the normal human hepatic cells (HL-7702). The pan caspase inhibitor zVAD-fmk did not inhibit the cytotoxic activity of ART. Electron microscopy of ART-treated cells revealed severe cytoplasmic swelling and vacuolization, swollen and internally disorganized mitochondria, dilation (but not fragmentation) of the nuclei without chromatin condensation, and cell lysis, yielding a morphotype that is typical of oncosis. The ART-treated cells exhibited a loss of mitochondrial membrane potential (ΔΨm) and ART-induced cell death was inhibited in the presence of the reactive oxygen species (ROS) scavenger N-acetyl-cysteine (NAC). Importantly, ART produced a dose-dependent tumor regression in an in vivo pancreatic cancer xenografts model. The in vivo antitumor activity of ART was similar to that of gemcitabine. Taken together, our study suggests that ART exhibits antitumor activity against human pancreatic cancer via a novel form of oncosis-like cell death, and that ART should be considered a potential therapeutic candidate for treating pancreatic cancer

An Artemisinin-Derived Dimer Has Highly Potent Anti-Cytomegalovirus (CMV) and Anti-Cancer Activities

We recently reported that two artemisinin-derived dimers (dimer primary alcohol 606 and dimer sulfone 4-carbamate 832-4) are significantly more potent in inhibiting human cytomegalovirus (CMV) replication than artemisinin-derived monomers. In our continued evaluation of the activities of artemisinins in CMV inhibition, twelve artemisinin-derived dimers and five artemisinin-derived monomers were used. Dimers as a group were found to be potent inhibitors of CMV replication. Comparison of CMV inhibition and the slope parameter of dimers and monomers suggest that dimers are distinct in their anti-CMV activities. A deoxy dimer (574), lacking the endoperoxide bridge, did not have any effect on CMV replication, suggesting a role for the endoperoxide bridge in CMV inhibition. Differences in anti-CMV activity were observed among three structural analogs of dimer sulfone 4-carbamate 832-4 indicating that the exact placement and oxidation state of the sulfur atom may contribute to its anti-CMV activity. Of all tested dimers, artemisinin-derived diphenyl phosphate dimer 838 proved to be the most potent inhibitor of CMV replication, with a selectivity index of approximately 1500, compared to our previously reported dimer sulfone 4-carbamate 832-4 with a selectivity index of about 900. Diphenyl phosphate dimer 838 was highly active against a Ganciclovir-resistant CMV strain and was also the most active dimer in inhibition of cancer cell growth. Thus, diphenyl phosphate dimer 838 may represent a lead for development of a highly potent and safe anti-CMV compound

Prevention of plant crown gall tumor development by the anti-malarial artesunate of Artemisia annua

Die antimalaria-aktive Substanz Artesunat, ein Sesquiterpen-Trioxan-Lacton-Derivat von Artemisinin, ist für seine außergewöhnlichen Hemmeffekte auf Plasmodien und Trematoden sowie die Unterdrückung der Proliferation von Tumorzellen bekannt. In der vorliegenden Untersuchung wurde die Wirkung von Artesunat auf sich schnell teilende Pflanzenzellen von Agrobacterium tumefaciens-induzierten Crown-Gall-Tumoren und Wundkalluszellen bei der Modellpflanze Ricinus communis untersucht. Niedrige, aber ständig applizierte Artesunatkonzentrationen (10 µM) reichten aus, um die Crown-Gall-Entwicklung vollständig zu unterdrücken. Innerhalb von drei Wochen erreichten die infizierten, aber mit Artesunat behandelten Pflanzen etwa die doppelte Größe der tumorisierten Pflanzen und zeigten ein reichlicheres und gesundes Blattwerk mit größeren Blättern. Artesunat verlangsamte auch die Wundkallusentwicklung und verursachte oberflächliche Nekrosen. Es verhinderte jedoch nicht die Infektion von Gurkenblättern durch echten Mehltau, Podosphaera xanthii, oder durch falschen Mehltau, Pseudoperonospora cubensis. Junge Gurkenblätter reagierten auf sehr hohe Artesunatkonzentrationen, 100 µM und höher, mit Nekrosesymptomen, jedoch nicht auf geringere Konzentrationen von 50 µM und niedriger. Diese neuartigen Befunde lassen auf einen allgemeinen und grundlegenden Wirkungsmechanismus von Artesunat bei menschlichen, tierischen und pflanzlichen Zellen schließen, nicht aber bei phytopathogenen Pilzen. Eine mögliche Anwendung von Artesunat im Biologischen Pflanzenschutz zur Verhinderung von Crown-Gall-Tumoren bei Reben (Mauke) oder wertvollen Obstbäumen wird diskutiert.The antimalarial drug artesunate, a sesquiterpene trioxane lactone derivative of artemisinin from Artemisia annua L., is known for its extraordinary inhibitory effects on plasmodia and trematodes and also for suppressing the proliferation of human tumor cells. In the present study the effect of artesunate was investigated on rapidly dividing plant cells in Agrobacterium tumefaciens-induced crown gall tumor and wound callus cells at the model plant Ricinus communis. Low concentrations of artesunate (10 µM) were sufficient to completely suppress crown gall development upon permanent application. Within three weeks the shoots of artesunate-treated plants attained about double the size of the tumor-bearing plants and showed abundant, healthy and larger leaves. Moreover, artesunate retarded wound callus development and induced superficial necroses. However, artesunate did not prevent or inhibit infections of cucumber leaves by powdery (Podosphaera xanthii) or downy mildew (Pseudoperonospora cubensis). Young cucumber leaves showed symptoms of phytotoxicity upon treatment with very high artenusate concentrations of 100 µM and higher. Lower concentrations (50 µM or less) did not cause visible necrotic lesions. These novel findings suggest a general and conserved basic mode of action of artesunate in human, animal and plant cells, except of phytopathogenic fungi. A possible application of artesunate for biological control of crown gall development in grapevine and precious fruit trees is discussed

Tumor-Specific Blood Serum Factors as Basis of Tumor Dormancy

In the present review, we focus on the importance of blood serum factors for tumor growth in vivo. Data from mice experiments indicate the existence of serum factors, which decrease the dormancy of Ehrlich carcinoma cells from 85 to 20%. The impaired production of these factors increases the life span of tumor-bearing animals from 14 days to 120 days. Blocking the production of tumor-specific factors causes the complete regression of already developed Ehrlich carcinoma. These serum factors do not affect the malignant carcinoma cells in vitro. We identified serpins as tumor dormancy serum factors. Experimental evidence suggests that serpins are not only essential for tumor growth. Serpins are also involved in the regeneration of normal tissues, such as adipose tissue, recurrence after cosmetic operations (liposuction), inhibiting rejection after liver transplantation, protection of parasitic flat worms living in host tissues and organs etc. We conclude that the inhibition of serum dormancy factor may represent attractive novel strategies for the prevention and treatment of relapsed cancers