Annie Panzer

The validity of melatonin as an oncostatic agent

ABSTRACT: The validity of melatonin as a prominent, naturally occurring oncostatic agent is examined in terms of its putative oncostatic mechanism of action, the correlation between melatonin levels and neoplastic activity, and the outcome of therapeutically administered melatonin in clinical trials. Melatonins mechanism of action is summarized in a brief analysis of its actions at the cellular level, its antioxidative functions, and its indirect immunostimulatory effects. The difficulties of interpreting melatonin levels as a diagnostic or prognostic aid in cancer is illustrated by referral to breast cancer, the most frequently studied neoplasm in trials regarding melatonin. Trials in which melatonin was used therapeutically are reviewed, i.e., early studies using melatonin alone, trials of melatonin in combination with interleukin‐2, and controlled studies comparing routine therapy to therapy in combination with melatonin. A table compiling the studies in which melatonin was used in the treatment of cancer in humans is presented according to the type of neoplasm. Melatonins suitability in combination chemotherapy, where it augments the anticancer effect of other chemotherapeutic drugs while decreasing some of the toxic side effects, is described. Based on the evidence derived from melatonins antiproliferative, antioxidative, and immunostimulatory mechanisms of action, from its abnormal levels in cancer patients and from clinical trials in which melatonin was administered, it is concluded that melatonin could indeed be considered a physiological anticancer substance. Further well‐controlled trials should, however, be performed in order to find the link between its observed effects and the underlying mechanisms of action and to define its significance as a therapeutic oncostatic agent.

Melatonin has no effect on the growth, morphology or cell cycle of human breast cancer (MCF-7), cervical cancer (HeLa), osteosarcoma (MG-63) or lymphoblastoid (TK6) cells

Melatonin was previously shown to inhibit proliferation of MCF-7 human breast cancer cells. In this study the effect of melatonin on MCF-7 cells was further examined, while human cervical carcinoma (HeLa), osteosarcoma (MG-63) and lymphoblastoid (TK6) cells were tested for the first time. Haemocytometer counts, DNA content, flow cytometry and indirect immunofluorescence for nucleolar proteins, actin and beta-tubulin showed no differences in the growth, cell cycle or morphology between melatonin-exposed and control cells. The direct antiproliferative effect of melatonin thus seems to be confined to a melatonin-responsive subclone of MCF-7 cells and not applicable to the majority of cancer cells.

The effects of chelidonine on tubulin polymerisation, cell cycle progression and selected signal transmission pathways.

Chelidonine is a tertiary benzophenanthridine alkaloid known to cause mitotic arrest and to interact weakly with tubulin. Our interest in chelidonine began when we found it to be a major contaminant of Ukrain, which is a compound reported to be selectively toxic to malignant cells. The effects of chelidonine in two normal (monkey kidney and Hs27), two transformed (Vero and Graham 293) and two malignant (WHCO5 and HeLa) cell lines, were examined. Chelidonine proved to be a weak inhibitor of cell growth, but no evidence for selective cytotoxicity was found in this study. It was confirmed that chelidonine inhibits tubulin polymerisation (IC50 = 24 microM), explaining its ability to disrupt microtubular structure in cells. A G2/M arrest results, which is characterised by abnormal metaphase morphology, increased levels of cyclin B1 and enhanced cdc2 kinase activity. Exposure of all cell lines examined to chelidonine leads to activation of the stress-activated protein kinase/jun kinase pathway (SAPK/JNK).

UkrainTM, a semisynthetic Chelidonium majus alkaloid derivative, acts by inhibition of tubulin polymerization in normal and malignant cell lines

Ukrain(TM) has been described as a semisynthetic Chelidonium majus alkaloid derivative, which exhibits selective toxicity towards malignant cells only. Its mechanism of action has hitherto been uncertain. We found that Ukrain(TM) inhibits tubulin polymerization, leading to impaired microtubule dynamics. This results in activation of the spindle checkpoint and thus a metaphase block. The effects of Ukrain(TM) on the growth, cell cycle progression and morphology of two normal, two transformed and two malignant cell lines did not differ. We could thus find no evidence for the selective cytotoxicity previously reported for Ukrain(TM).

The antimitotic effects of Ukrain™, a Chelidonium majus alkaloid derivative, are reversible in vitro

Ukrain is alleged to be an effective chemotherapeutic drug which causes minimal side-effects as a result of selective toxicity towards malignant cells only. We previously failed to confirm this claim and found Ukrain to be equally toxic to normal, transformed and malignant cell lines by causing a metaphase arrest. In this study we have found the antimitotic actions of Ukrain to be reversible in low doses in vitro, as shown by flow cytometry and concurrent haematoxylin and eosin stains. We hypothesize that the lack of side-effects found in vivo may be due to the lack of therapeutically effective dosages being administered, therefore enabling cells to overcome the metaphase arrest and survive.

The effects of prostaglandin A2 on cell growth, cell cycle status and apoptosis induction in HeLa and MCF-7 cells

The effects of 20 microg/ml exogenous prostaglandin A(2) (PGA(2)) were evaluated on cell numbers in HeLa (human epithelial cervix carcinoma) and MCF-7 (human breast carcinoma) cells. In HeLa cells, PGA(2) reduced cell numbers significantly to 75% after 24 h (P < 0.05) and exposure of 48 h decreased cell numbers to 61% (P < 0.05) of the control. In MCF-7 cells, PGA(2) significantly reduced cell numbers to 48% after 24 h and to 20% after 48 h, compared to vehicle-treated control cells (P < 0.05). The anti-mitogenic effects were confirmed by morphological studies conducted after 48 h of exposure to PGA(2), when optimal effects were observed. HeLa and MCF-7 cells exposed to PGA(2), showed chromatin aggregation, cell membrane blebbing and uneven distribution of chromosomes. Cell cycle progression analysis of HeLa and MCF-7 cells, showed an increase in DNA content preceding the G(0)/G(1) peak after 48 h of exposure, which is indicative of apoptotic body formation.

Depression or cancer: the choice between serotonin or melatonin?

Stress causes disturbances of monoamine functioning and may result in a serotonin deficiency which is manifested, as depression. In some humans, stress does not, however, cause depression. It is hypothesized that in these individuals, melatonin, which is normally a product of serotonin, may be converted back to its precursor and thus replenish serotonin stores. These people are thus not depressed and are characterized by their pleasant, unassertive nature. Their lowered melatonin levels may, however, signal an increased risk for cancer. It is therefore postulated that unresolved stress results in either depression (with low serotonin) or cancer (as a result of decreased melatonin), depending on individual personality traits and biochemistry.

Associations between psychological profiles and diseases: examining hemispheric dominance and autonomic activation as underlying regulators

Personality profiles are often typical for specific illnesses, e.g., the type A personality and heart disease. We hypothesize that many more such patterns exist, and have developed a scheme in which many diseases can be classified, depending on hemispheric dominance (i.e., integrated, intellectualising or emotional) and type of autonomic control (i.e., dominance of either sympathetic or parasympathetic system, or an increase in both types of autonomic outflow). Our hypothesis is based on recent findings in neurophysiology, involving the early rearing environmental effects on the developing orbitofrontal cortex, and attachment theory. We conclude with implications for therapy, and a discussion of the limitations of our hypothesis.

Chemical analyses of Ukrain, a semi-synthetic Chelidonium majus alkaloid derivative, fail to confirm its trimeric structure.

Ukrain has been described as a semi-synthetic Chelidonium majus alkaloid derivative, consisting of three chelidonine alkaloids combined to triaziridide. We found the actions of Ukrain to be similar to the Chelidonium alkaloids it is prepared from, and therefore became concerned about its chemical integrity. Chemical analyses of Ukrain by thin layer chromatography, high-performance liquid chromatography and liquid chromatography-mass spectrometry was inconsistent with the proposed trimeric structure and demonstrated that at least some commercial preparations of Ukrain consist of a mixture of C. majus alkaloids (including chelidonine).

Melatonin in osteosarcoma: an effective drug?

The pineal indole amine melatonin has been shown to have oncostatic properties in a wide variety of neoplasms. Melatonin levels start to diminish before the onset of puberty and continue to decline during puberty. There appears to be a relationship between the rate of bone growth and the incidence of osteosarcoma (which was found to be highest in the long bones of the leg in the 10-14-year age group). It is hypothesized that the simultaneous decrease in melatonin levels (with diminishing oncostatic protection), concurrent with the exponential increase in bone growth during puberty (i.e. increased rate of cell proliferation), could be a factor in the typical age distribution of osteosarcoma. Melatonin is of value in combined chemotherapy, because it is non-toxic and can augment the anti-cancer action and decrease the side-effects of many other chemotherapeutic drugs. It is hoped that melatonin, as an adjunct to the routine chemotherapy of osteosarcoma, will help to improve the prognosis of this too often fatal disease.