Abstract
Catharanthus roseus is a plant of the Apocynaceae family. It produces over 120 alkaloids, 70 of which are pharmacologically active. C. roseus produces vinblastine, utilized in treating Hodgkin’s disease; testicular tumors, breast carcinoma, choriocarcinoma, Kaposi sarcoma and Letterer-Siwe disorder. Vincristine is used to treat acute lymphocytic leukemia, lymphosarcoma, lympho-granulomatosis and in solid infant tumors. The preparation process of 1 kg of vincristine has a cost of US$ 3.5 million, while vinblastine has a cost of US$1 million. Therefore, 530 kg of dry leaves are necessary to produce 1 kg of vincristine and half a ton for getting 1 g of vinblastine. The high cost is due to the low concentrations in the aerial portion. Due to the high market value and its effectiveness in different medical treatments, this chapter deals with the pharmacological application of the C. roseus alkaloids.
Keywords
- antileukemic
- indole-monoterpene alkaloids
- Letterer-Siwe disorder
- vinblastine
- vincristine
1. Introduction
2. Phenotypic characteristics of Catharanthus roseus
3. Mechanism of biological action
Vincristine and vinblastine are potent mitotic inhibitors used in leukemia chemotherapy; they are structures hard to synthesize chemically, like other cancer-fighting drugs such as taxol [21] thus biotechnological approaches represent the best route for its obtention. Vincristine binds to the tubulin β-subunit, the precursor protein of microtubules responsible of mitosis and other essential cellular functions like substrate transport, cellular mobility, and structural integrity, and it inhibits microtubule formation—this disruption causes cellular death and mitosis arrest [22].
4. Biosynthesis of terpenoid indole alkaloids of Catharanthus roseus
It has been shown that the biosynthesis of terpenoid indole alkaloids (TIA) in
4.1 Vindoline formation
Strictosidine β-d-glucosidase (SGD) is the enzyme that performs an important role in guiding monoterpenoid indole alkaloids biosynthesis in a specific direction. The elimination of the rest of the glucose of strictosidine by SGD leads to an unstable, highly reactive aglucone, that is believed to convert into 4,21 dehydrogeissoschizine. It is believed that the latter is converted into cathenamine by the cathenamine synthase. Cathenamine is then converted into tabersonine through several steps, transforming into vindoline by a six-step sequence [28].
4.2 Regulation of tdc, str-1, d4h, and dat genes in Catharanthus roseus
Gene and enzyme regulation participating in TIA biosynthesis in
4.3 tdc and str1 genes
In
In cell cultures of
The expression of the promoter of the gene str1 in transgenic cellular cultures of
4.4 d4h and dat genes
In
5. Pharmacological application of Catharanthus roseus alkaloids
5.1 Clinical pharmacology
Vinblastine is a drug used in the elective regime for the metastatic treatment of testicular cancer. The estimates of half-life after vinblastine administration to patients were 4 min, 1.6 h, and 25 h, which indicates a faster drug distribution in most tissues and a subsequent slower terminal elimination process. Distribution and initial cleaning phase for vincristine are kinetically comparable to the ones observed for vinblastine; half-lives for those phases have been reported at 4 min and 2.3 h in studies with vincristine. The terminal elimination phase for vincristine is reported to be three to four times longer than the one estimated for vinblastine, and the slow elimination of vincristine from the neuronal susceptible tissue suggest that it plays a role in neurotoxicity commonly seen in clinical adjustments with vincristine but not with vinblastine [35]. Hepatic metabolism and bile excretion play major roles in the elimination of both vinblastine and vincristine in humans [36]; small quantities of vincristine and vinblastine, in the order of 10% of the administered dose, are excreted with no alterations through urine. The renal clearance of vinblastine is reported as being less than 10% of the total elimination of the serum [37]. It has been reported that vinblastine inhibits a polymorphic cytochrome P-450 in human hepatic microsomes, but the necessary concentrations were higher than those observed in clinical adjustments [38]. It is recommended that vinblastine and vincristine doses must be reduced in patients with liver disease. Vincristine is conventionally administered intravenously, in adults, with a dose of 1.4 mg/m2, the total dose must not exceed 2 mg in each administration. Sulkes and Collins have commented on the adjustments that can be provided for conventional doses of vincristine and other drugs [39]. Of particular importance is the possibility that some patients can show a good clinical response and relatively low toxicity in dose regimes involving the cautious use of large quantities of vincristine. The initial dose of vinblastine for adults is 3.7 mg/m2, with a range of the typical growing dose of 5.5–7.4 mg/m2, administered weekly [37, 38].
5.2 Antidiabetic activity
Considering the traditional use against diabetes,
Soon et al. [43] found that the dichloromethane leaf extract of
5.3 Antileukemic activity
Vincristine is employed to treat lymphocytic acute leukemia (the most frequent malign hemopathy in childhood), of which several chromosomic alterations with prognostic importance are known. Among them there are the translocation (4;11) and the translocation (9;22), which are indicators of a bad prognosis, while hyperdiploidy is associated with a good prognosis [44] and it attacks lymphomas including solid tumors in children.
5.4 Antioxidant enzymatic activity
An experiment with different concentrations of sodium chloride in two varieties of
5.5 Antiviral activity
Ozcelik et al. [46] showed the antiviral effect of
5.6 Hypoglycemic activity
It was shown in several animal studies, that ethanolic leaf and flowers extracts decreased the levels of glucose in blood. Hypoglycemic effects are a result of increasing the use of glucose in liver [47]. The aqueous extract decreased glucose in blood in approximately 20% of diabetic rats, compared to methane and dichloromethane extracts in which glucose in blood decreased 49–58% [48]. In the present there are new alkaloids that have been studied in the
5.7 Antidiarrhoeic in vivo activity
The antidiarrhoeic
5.8 Antimicrobial activity
The antimicrobial activity of leaf extracts was tested against microorganisms such as
The results indicated that leaf extracts showed a higher antibacterial activity than the extracts prepared from other parts of the
5.9 Antineoplastic effect
6. Extraction and analysis of alkaloids of Catharanthus roseus
The extraction method of terpenoid indole alkaloids in
Some effective alkaloid extraction methods have been identified from pilose roots of
7. Generalities of the in vitro culture
The general process of the
In addition, several studies modify the pH of the culture media to increase the release of secondary metabolites, and few studies have been carried out to examine the effects of buffers in plant culture growth or in secondary metabolism biosynthesis pathways. Several authors have studied the effect of buffers in
Light is a very important factor in the
7.1 In vitro culture of alkaloid production of Catharanthus roseus
It stands out that among the major advantages of plant cell and tissue cultures in basic research, of micropropagation and production of compounds with biologic activity such as secondary metabolites, proteins, and transgenic products, they allow studies in a shorter time and under more controlled conditions than the ones used in traditional methods. A callus is defined as a groups of dedifferentiated friable cells growing in a solid medium and it is the initial material for the establishment and growth of suspension cells. The obtained calli can be subcultured for its maintenance and propagation or induced into differentiation to form organs (organogenesis), embryos (embryogenesis) or to be transferred into a liquid culture medium to obtain cells and small aggregates in suspension. The
There are different
Several
Mekky et al. [66] cultured leaves of
8. Conclusions
Acknowledgments
This work was supported by the “Programa para el Desarrollo Profesional Docente” PRODEP-Mexico of the project 2017-2018 of Hebert Jair Barrales-Cureño PhD of the Universidad Intercultural del Estado de Puebla.
List of abbreviations
BAP | 6-Benzylaminopurine |
CAS | Cerium Ammonium Sulfate |
Gb | Gibberellin |
HPLC | High-Performance Liquid Chromatography |
IAA | Indole-3-acetic acid |
KIN | Kinetin |
NAA | 1-Naphthaleneacetic acid |
TIA | Terpenoid indole alkaloids |
TLC | Thin Layer Chromatography |
VLC | Vacuum Liquid Chromatography |
2,4-D | 2,4-Dichlorophenoxyacetic acid |
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