(1) Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Taiwan
(2) Graduate Institute of Natural Products, Chang Gung University, Taiwan
(3) Department of Molecular Biology and Human Genetics, Tzu Chi University, Taiwan
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Uncontrolled cell proliferation is a common feature of human cancer. Most of the drugs used currently in therapeutics strategies are classified as antiproliferative drugs via apoptosis pathway. Mitotic catastrophe is a distinct non-apoptotic mechanism often triggered in cancer cells and tissues in response to anti-cancer drugs. As of date, little research exists to show Herbal extracts or plant-derived medicines are an important source of effective anti-cancer agents, particularly for treating mitotic catastrophe. This article explores how mitotic catastrophe is triggered by
For the past five years, we have been investigating the anti-cancer effects of
Research on medicinal plants has shown that they are an important source of effective anti-cancer agents. More than half of the drugs used in clinical trials for anti-cancer activity are derived from natural sources.
In one of the above cases,
The authors have referenced some of their own studies in this review. The protocols of these studies have been approved by the relevant ethics committees related to the institution in which they were performed.
Schmidt et al. carried out a study to establish the biological properties of Brazilian plants used in wound healing. By studying the different bioassays identified, Schmidt et al. found that KT did not show much promise as a potential treatment agent. In fact, KT showed a toxic effect in the MTT assay. This is consistent with the findings of our study. Toxicity of KT was tested in different cell lines and different dosages. The cell viability for all cell lines was found to be 20% below the concentration level of 20μg/ml. Hence, there is sufficient evidence to suggest that KT extract effectively inhibits growth of different cancer cell lines.
The scratch assay in Schmidt’s study showed that the n-hexanic extract of KT had no activity in the scratch assay at a concentration of 10μg/ml. The ethanoic extract showed a moderate ‘wounding-healing’ effect. However, in our study we found that KT extract completely blocked ‘wound healing’ at a concentration of 50μg/ml. Note that the scratch assay does not distinguish between migration and proliferation. However, in terms of anti-cancer activity, KT is a promising agent for anti-proliferation and/or anti-migration.
Mitosis is a highly coordinated process in which two copies of one chromosome are moved away from each other to the opposite poles of cells. Sister-chromatid segregation depends on a complex molecular scaffold of the mitotic spindle. Disruption of the mitotic spindle structure precludes proper alignment of chromosomes and activates the spindle assembly checkpoint and mitotic arrest, which in turn provides time for cells to correct the attachment error between the microtubule and kinetochore. However, prolonged mitotic delay is often followed by cell death in mitosis. This is the strategy to kill cancer cells by perturbing mitotic spindle assembly. Microtubules play an important role in cell proliferation, trafficking and migration. Microtubules are a basic component of mitotic spindle. This is why agents that bind to microtubules are used in cancer therapy. Two clinical anti-cancer drugs, taxanes and vinca alkaloids, are natural products that affect microtubule dynamics and cause abnormal spindle formation[10,11,12]. However, microtubules are also present in interphase cells. Microtubule binding agents also perturb the micro-tubule network of interphase cells and cause neurotoxic effects.
The microtubule binding agents have side-effects unrelated to antimitotic effects. This warrants searching for more mitosis-selective drugs. The mitotic-selective approach targets proteins that function only in mitosis. Some of the drugs that target the six mitotic proteins are currently undergoing clinical trials. These mitotic proteins include two motor proteins (Eg5, CENP-E) and four kinases (Aurora A, Aurora B, Cdk1, Plk1)[14,15]. Eg5 is a plus end-directed motor protein that drives centrosome separation in prophase. Inhibition of Eg5 results in monopolar spindles causing mitotic arrest in a spindle-assembly-checkpoint-dependent manner[17,18]. CENP-E is a kinetochore-associated protein that stabilizes the interactions between microtubules and kinetochore during mitosis. It functions exclusively in mitosis. Inhibition of CENP-E leads to misaligned chromosomes in meta-phase. CDK1 is the main regulator for mitotic entry in mammalian cells. Plk1, Aurora A and Aurora B regulate mitotic entry and ensure that chromosome segregation and cytokinesis events take place.
In our previous study, we found that KT extract also has the capacity to arrest cells in the G2/M phase. Drugs that bind to microtubules are able to arrest cells in G2/M. However, KT extract does not disturb the microtubule organization in interphase or spindle formation in mitosis. Instead, KT extract treatment resulted in multipolar spindles (Figure 1A) and chromosome misalignment (Figure 1B). These defects activate mitotic checkpoints and cause mitotic arrest. The arrested mitotic cells are often followed by cell death in mitosis. Some of the mitotic defective cells could exit mitosis and end up in a tetraploid or aneuploid state. The fate of those mitotic checkpoint slippage cells could be apoptosis, senescence or necrosis. Various compounds isolated from KT have been summarized in this critical review (Table 1)[8,25].
Mitotic cells. (A) A cell with multipolar spindle. (B) The chromosomes of a metaphase cell. Arrow points to the misalignment of chromosomes.
Phytochemicals isolated from
Finding ways to develop traditional herbal medicine is a matter of great urgency. Plants have chemical defence mechanisms that synthesize a wide variety of compounds that can be used to perform important biological functions and to defend against attack from predators. Many of these phytochemicals have beneficial effects, but some can have adverse or lethal effects on humans. However, no single chemical can effectively treat human diseases without side-effects. Isolation, identification and bioactive tests of pure compounds are standard strategies utilized in studying natural products. In many cases, scientists are not sure what specific ingredient in a particular herb can treat diseases. Whole herbs contain many ingredients that likely work together to produce a beneficial effect. Herbalists tend to use extracts from different parts of plants, such as roots or leaves, but do not isolate particular phytochemicals. They often reject the notion of a single active ingredient, arguing that the different phytochemicals present in many herbs will interact to enhance the therapeutic effects of the herbs and dilute toxicity. However, the activities of compounds isolated from plants are not necessarily parallel to the phenotypes observed in the traditional use of these plants.
A major aspect of traditional Chinese medicine focuses on restoring the homeostasis of the body to maintain health rather than treating a particular disease or medical condition. If used correctly, herbs can cure a variety of conditions, and in some cases, may have fewer side-effects than some of the conventional medications. Here we would like to draw an open question. Shall we keep doing separation? In understanding the role of medicinal herbs in human physiology, one might end up with putting all the isolated components together in order to reveal how therapy works. Hence, we still have a long way to go in determining the most effective modalities of treatment that uses medicinal herbs. More scientific data and evidence-based research are needed to determine the effectiveness of medicinal herbs.
All authors contributed to the concept on, design, and preparation of the manuscript, as well as read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Phytochemicals isolated from
|I Flavonoids||III Steroids|
|II Benzenoids||Kalantuboside A|
|Trans-ferulic acid||Kalantuboside B|
|Syringic acid||Bryotoxin C|
|Vanillic acid||IV Others|
|Methyl gallate||Taurolipid C|