Uncontrolled cell proliferation is a common feature of human cancer. Kalanchoe and some herbal extracts or plant-derived medicine had been shown to be an important source of effective anticancer agents.
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We previously reported that an n-BuOH-soluble fraction of Kalanchoe tubiflora has antiproliferative activity by inducing mitotic catastrophe.
In this study, we showed that the H2 O-soluble fraction of Kalanchoe tubiflora (KT-W) caused cell cycle arrest and senescence-inducing activities in A549 cells.
We used 2-dimensional Pages to analyze the protein expression levels after KT-W treatment and identified that the energy metabolism-related proteins and senescence-related proteins were disturbed.
In vivo experiments showed that the tumor growths in A549-xenografted nude mice were effectively inhibited by KT-W. Our findings implied that KT-W is a putative antitumor agent by inducing cell cycle arrest and senescence.
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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.
Kalanchoe is a genus of the Family Crassulaceae. Various species of Kalanchoe are used medicinally in Southeast Asia, specifically Indo-China and the Philippines.
Plants of this genus are mentioned in folklore and are used as traditional medicines for treating fever, abscesses, bruises, contused wounds, coughs, skin diseases, infections, hypertension, rheumatism, and inflammation and, in particular, tribes in the state of Kerala, India, use these plants for treating cancer symptoms.
A variety of bufadienolide compounds have been isolated from various Kalanchoe species, which showed strong antitumor-promoting activity
In one of the above cases, Kalanchoe hybrida was used. It is the hybrid of Kalanchoe daigremontiana and Kamānche tubiflora (KT) and is naturalized throughout the island of Taiwan.
On the basis of the aforementioned studies, KT, one of the original sources of the hybrid, was selected as a target given its biological activities. KT is used as a wound-healing agent in traditional South Brazilian medicine.
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Few cardenolides and bufadienolide glycoside compounds were isolated from KT in Kuo group. Four of the isolated compounds have the capacity to arrest HL-60 cells in G2/M phase. In our study, we used KT as an example to discuss agents that target mitotic cells.
Anti-cancer activity
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. The 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 the 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.
Anti-cancer mechanism
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, the 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.
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.
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These mitotic proteins include two motor proteins (Eg5, CENP-E) and four kinases (Aurora A, Aurora B, Cdk1, Plk1). 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.
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).
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These defects activate mitotic checkpoints and cause mitotic arrest. The arrested mitotic cells are often followed by cell death in mitosis.
Some 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.
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