Haemoglobinization of leukaemia cells
The biological activity of alkaloids can be demonstrated by fagaronine (Figure 82), an alkaloid isolated from Fagara zanthoxyloides Lam. (Rutaceae). This alkaloid alone has been tested by many research groups as biological agent of the haemoglobinization of human leukaemic cells372'373'374'375'376. One of the characteristics of leukaemic cells is escaping the normal regulatory pathway controlling cell proliferation and differentiation. As early as in 1972, Messmer et al.372 reported on fagaronine anti-leukaemic activity against murine leukaemia P388. Four years later, Sethi373 published a study with evidence indicating that fagaronine inhibits DNA polymerase activity in murine embryos. It was also found that fagaronine inhibits human DNA ligase I377 and reverse transcriptases from RNA viruses378. This last finding was also confirmed by Tan et al.379 in the case of human HIV-1 reverse trascriptase in vitro. In the year 1983, Pezzuto et al.374 reported that fagaronine inhibits nucleic acid and protein synthesis in KB cells. Fagaronine was also reported to induce the haemoglobinization of leukaemic K562 cells375. Later studies pointed to the ability of this alkaloid to intercalate DNA, to interact with the ribosomal system380 and to inhibit the activities of the DNA topoisomerase I and II381382. The research group of Dupont in France has examined the effect of fagaronine on erythroid differentiation and growth of leukaemic K562 cells376.
The results of this deep research can be considered promising in the field and they are also in agreement with results obtained in previous studies by Comoe et al.375. Dupont et al.376 observed that fagaronine induces the homoglobinization of K562 cells and inhibits leukaemic cell growth in 80% of cells. Moreover, fagaronine has no acutely toxic effects on the K562 cell line376. The mechanism of this biological influence was explained by Dupont et al.376 as resulting from
the action of several genes. Haemoglobin synthesis mediated by fagaronine treatment was preceded by the increased transcription of several genes known as the markers of erythroid differentiation. They are a- and ft-globins, PBGD and EPO-R. Moreover, haemoglobin synthesis in leukaemic cells was preceded also by an over-expression of GATA-1 and NF-E2 mRNAs as well as by GATA-1 protein accumulation376. Haemoglobin is a known tetramer of protein sub-units with two a and two ft sub-units, myoglobin and two glutamic acid residues in ft sub-units. A haeme is an iron-containing porphyrin acting as a prostethic (Figure 83). Moreover, fagaronine has caused increased transcriptional activity of the luciferase gene downstream of the a-globin, EPO-R and GATA-1 promoters. This study is very interesting and proved that alkaloids have strong biological activities in foreign organisms. In this respect, fagaronine has probably more activity than in F. zanthoxyloides, a plant producing it, although this is only a hypothesis. The biological activity of fagaronine in plant cells is under-studied in comparison to that in human cells. Its activity in plant cells should not be dismissed, for it may provide a better understanding of fagaronine activity in human cells.
There are presently many other studies on alkaloid bioactivity in human leukaemia cells and the role of alkaloids as competitive antagonists of cytotoxic agents383 384. Sampangine, for example, is an alkaloid extracted from the stem bark of Cananga odorata. Kluza et al.383 show that the treatment of human HL-60 leukaemia cells for 48 hours with sampangine induced oxidative processes and proved that this alkaloid has anticancer properties. Another alkaloid, voacamine, extracted from Peschiera fuchsiaefolia has been evidenced as an inhibitor to P-glycoprotein action and a competitive antagonist of cytotoxic agents384.
Pitzalis et al.385 have studied the influence and molecular alternation of retrorsine on rat hepatic cell cycle. Retrorsine has been found to block proliferation of resident cells. Cyclin D1 mRNA and protein levels were found to be elevated in rats treated with this alkaloid. The PCNA was also elevated385.
The conclusion from this study is that such a persistent block outside the resisting phase may contribute to selective replacement of resident cells during liver repopulation.
The haemoglobinization of human leukaemic cell lines by alkaloids demonstrated through in vitro means that these compounds are biologically very active. Alkaloids are therefore a promising botanical to be used in future applications.
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