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Several diverse compounds were isolated under a project entitled "Novel strategies for plant derived anticancer agents" with a National Co-operative Drug Discovery Group (NCDDG) programme of the National Cancer Institute (NCI), USA. Several of these compounds are currently under investigation for their anticancer activity including betulinic acid, pervilleine A and silvestrol [20].

Cephalotaxus harringtonia (Cephalotaxaceae, Gymnosperm) contains several alkaloids - deoxyharringtonine, harringtonine, homoharringtonine, and isoharring-tonine - that have shown anticancer activity against leukaemia in mice.

Homoharringtonine affects a number of cellular pathways leading to apoptosis and angiogenesis [104]. A synthetic derivative of homoharringtonine is in phase II clinical trials for the treatment of patients with chronic myeloid leukaemia that is resistant to the first line therapy, Gleevec [105].

The combretastatins obtained from Combretum caffrum are from a class of polyphenolics known as stilbenes, which act as anti-angiogenic agents, causing vascular shutdown in tumours and resulting in tumour necrosis [106]. Its water-soluble derivative combretastatin A4 phosphate, a disodium phosphate prodrug of combre-tastatin A4, is in phase II clinical trial [62]. The drug is effective against anaplastic thyroid cancer and myopic muscular degeneration and is currently in phase II clinical trials [107]. Combretastatin is a vascular targeting agent; it destroys tumour vasculature by inducing morphological changes within the endothelial cells [95, 108].

Phenoxodiol, a synthetic analogue of diadzein, an isoflavone present in members of the family Fabaceae (Pueraria tuberosa, Glycine max), is being developed for the treatment of cervical, ovarian, prostate, renal and vaginal cancers [109]. Phe-noxodiol is a broad-spectrum drug that induces cancer cell death through inhibition of anti-apoptopic proteins, including XIAP and FLIP [110]. The drug is in phase II and phase III clinical trials in the USA and Australia, respectively [111].

Betulinic acid, a lupane type triterpene widely distributed in the plant kingdom, and its derivatives are potential anticancer and anti-HIV agents, presently in clinical trials [112]. Recent evidence indicates that betulinic acid possesses broad-spectrum anticancer activity against several cancer cell types [8].

10.5 Mechanism of Action

Most of the antineoplastic compounds act upon DNA by modifying its chemical and physical nature. Broadly speaking, all the drugs can be categorised as alkylat-ing agents such as cisplastin, antimetabolites, e.g. 5-flurouracil and methotrexate, mitotic inhibitors which include vincristine, taxol and colchicines, and lastly DNA intercalating drugs like actinomycin-D [9].

Cancer is a complex disease. Mostly cancer is diagnosed late during the final stages of carcinogenesis, i.e. angiogenesis and metastasis. Chemically diverse compounds have different properties that act and react with cell metabolism. A better understanding of the process of cell division and how different compounds affect tubulin formation have a direct bearing on cancer treatment. The chemopreventive role of dietary molecules has been presented above. Molecules affecting all three phases of cancer, particularly metastasis, are in demand. Increasingly evidence suggests such a multidimensional role of resveratrol. Resveratrol is also able to activate apoptosis, to arrest the cell cycle, or to inhibit kinase pathways [45]. Drug designs, based on the structure of specific enzymes playing a role in carcinogenesis (tyrosine kinase) or DNA replication (topoisomerases II), have been successful at identifying novel effective anticancer drugs. In addition, many natural products are effective inhibitors of NF-kB, a cancer, indicating that the source of these compounds

Fig. 10.4 Binding sites of antimitotic drugs to microtubules. Paclitaxel binds along interior surface of microtubule. Binding of these compounds results in suppression of microtubule dynamics (adapted from [115] with permission)

might possess antitumour properties. [113]. This has resulted in the discovery of Gleevec, an inhibitor of the bcr-abl protein tyrosine kinase, for the treatment of chronic myeloid leukaemia [114].

Microtubules, the principal components of the cytoskeleton, are long, filamentous, tubular protein polymers that are essential in all eukaryotic cells. They play a crucial role in the maintenance of cell shape, in cell signalling and in cell division. Microtubules are composed of a- and P-tubulin heterodimers (100,000 dalton in mass) arranged in the form of cylindrical tubes several microns long [115]. Micro-tubules are involved in the separation of duplicated chromosomes of a cell during mitosis. This makes them an important target for anticancer drugs. Chemical compounds that interfere with microtubules, such as vinca alkaloids and taxanes, are important chemotherapeutic agents for the treatment of cancer. Vincristine, taxol and other mitotic inhibitors bind to specific sites on the microtubules (Fig. 10.4). The anticancer activity of microtubule-targeting drugs lies in their inhibitory effects on spindle microtubule dynamics, rather than their effects on microtubule polymer mass [116]. There is increasing evidence showing that even minor alterations in microtubule dynamics can engage the spindle checkpoint, arresting cell cycle progression at mitosis and eventually leading to apoptotic cell death (Fig. 10.5). Mi-crotubules as a target for anticancer drugs are discussed elsewhere in an excellent review [115].

Several new microtubule-targeting agents have shown potent activity against the proliferation of various cancer cells, including cells that show resistance to the existing microtubule-targeting drugs. Microtubule-interacting agents can be grouped

Fig. 10.5 Human osteosarcoma cells in different stages of cell cycle with and without addition of antimitotic drugs. Microtubules are shown in red, chromosomes in blue and kinetochores in green. A-D showing prophase, metaphase, anaphase and telophase stages of cell division. In presence of paclitaxel E and vinflunine F cell division is disturbed resulting in blocking of mitosis (adapted from [91] and [127])

Fig. 10.5 Human osteosarcoma cells in different stages of cell cycle with and without addition of antimitotic drugs. Microtubules are shown in red, chromosomes in blue and kinetochores in green. A-D showing prophase, metaphase, anaphase and telophase stages of cell division. In presence of paclitaxel E and vinflunine F cell division is disturbed resulting in blocking of mitosis (adapted from [91] and [127])

into two distinct functional classes: (i) compounds which inhibit the assembly of tubulin heterodimers into microtubule polymers (tubulin polymerisation inhibitors, e.g. vincristine, vinblastine) and (ii) compounds which stabilise microtubules under normally destabilising conditions (microtubule stabilisers, e.g. paclitaxel). A variety of diverse natural compounds have been shown to possess a taxol-like ability to inhibit depolymerisation of microtubules, such as epothilones-A and B, discodermolide, eleutherobin, sarcodictyins-A and B, laulimalide, cyclostreptin, peloruside A and dictyostatin [73]. The effectiveness of microtubule-targeting drugs for cancer therapy has been impaired by various side effects, particularly neurological and hematological toxicities [116].

Another approach utilises the ability of several compounds, especially microtubule-targeting agents, to rapidly shut down existing tumour vasculature [95]. Since the late 1990s, the combretastatins and N-acetylcolchicine-0-phosphate, compounds that resemble colchicines and bind to the colchicine domain on tubu-lins, have been developed as antivascular agents and are in clinical trials, e.g. combretastatin-A-43-O phosphate, combretastatin A-1 phosphate, ZD6126, AVE 8062A, and TZT-1027 (Table 10.1) [115].

10.6 Herb-Drug Interactions

The use of complementary and alternative medicines (CAM) by cancer patients in the western world has grown rapidly in recent years [117]. Generally, cancer patients are using CAM with conventional therapy, but more than 72% of them do not inform their treating physician about CAM [118]. CAM-anticancer drug interactions can occur at the pharmaceutical, pharmacodynamic, or pharmacokinetic level [119]. Interactions at pharmacokinetic level involve changes in absorption, distribution, metabolism, or excretion of the chemotherapeutic drug. One of the best known examples of a clinically significant effect of CAM on the pharmacokinetics of chemotherapeutic drugs is the herbal product, St. John's Wort (SJW) [120].

Pharmacokinetic interactions between CAM and oncolytic drugs occur when CAM inhibit or induce the metabolising enzymes (e.g. cytochrome P450 enzymes, phase II enzymes, dihydropyrimidine dehydrogenase) or drug transporters (e.g. p-glycoprotein, breast cancer resistant protein, multidrug resistance associated proteins) involved in the pharmacokinetic disposition of chemotherapeutic drug [117].

In vitro studies have been performed to investigate the potential of CAM to activate nuclear receptors and to induce metabolising enzymes. Such activities have been shown by apigenin, curcumin, garlic, ginseng, kava-kava, quercetin, resvera-trol, silymarin [121], guguggulsterone [122,123] and several others [117]. Based on current available information Meijerman et al., 2006 suggested that CAM like SJW, grape fruit juice, vitamin E, quercetin, ginseng, garlic, P-carotene and Echinacea should be taken with care along with anticancer therapy as these CAM can cause changes in drug metabolising enzymes.

10.7 Conclusions

Drug development is a long and expensive process and due to this reason, several pharmaceutical companies reduced their expenses on research and development for drug discovery from natural sources. From the above discussion, it is very much clear that natural resources, particularly plants, are an excellent source of life saving drugs. New compounds are also being discovered from lichens, microorganisms and marine organisms. Therefore, efforts are required to collaborate internationally in an attempt to isolate, identify and establish biological/ pharmacological properties of molecules [124]. New tools like high-resolution NMR, Mass spectrophotometers, and 2-D HPLC are helpful in identifying a plethora of molecules from plants and microorganisms. HTS systems are capable of evaluating a large number of bioactive molecules on various bioassays. At the same time, it is necessary to conserve traditional and folk knowledge about use of medicinal plants, and develop appropriate technology to conserve the plants. It is urgently required to investigate plants used in traditional medicine for the complete spectra of primary and secondary metabolites, and where a cocktail of plants is used, the effect of this cocktail on molecular reorientation may be explored. What we know is still a tip of the iceberg, we have yet to explore the entire biological world for novel leads.

A combination of two and more anticancer drugs such as taxol with vinblastine has been reported to effectively control the cancer growth and improved quality of life in patients suffering from hormone refractory prostrate cancer [125]. Additive and synergistic laboratory interactions with other cytotoxic drugs have been exploited to allow development of etoposide based multidrug regimens, which are showing promising activity in several malignancies [126]. Herbs and their preparations can play important role in increasing the efficacy of established drug, reducing suffering of the patients and to certain extend, increasing the longevity of life.

Acknowledgements Research on medicinal plants in the laboratory is supported by funds from UGC under DRS programme and DST under FIST programme. SG thanks UGC for fellowship.


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