Cancer:
Leukemia, oral squamous cell carcinoma, melanoma
Action: Cytotoxic, MDR, apoptosis-triggering, inhibits proliferation
Sanguinarine, chelerythrine and chelidonine are isoquinoline alkaloids derived from the greater celandine. They possess a broad spectrum of pharmacological activities. It has been shown that their anti-tumor activity is mediated via different mechanisms, which can be promising targets for anti-cancer therapy. This study focuses on the differential effects of these alkaloids upon cell viability, DNA damage, and nucleus integrity in mouse primary spleen and lymphocytic leukemic cells, L1210.
Data suggests that cytotoxic and DNA-damaging effects of chelerythrine and sanguinarine are more selective against mouse leukemic cells and primary mouse spleen cells, whereas chelidonine blocks proliferation of L1210 cells. The action of chelidonine on normal and tumor cells requires further investigation (Kaminsky, Lin, Filyak, & Stoika, 2008).
MDR
Cancer cells often develop multi-drug resistance (MDR) which is a multidimensional problem involving several mechanisms and targets. This study demonstrates that chelidonine, an alkaloid extract from Chelidonium majus, which contains protoberberine and benzo[c]phenanthridine alkaloids, has the ability to overcome MDR of different cancer cell lines through interaction with ABC-transporters, CYP3A4 and GST, by induction of apoptosis, and cytotoxic effects.
Chelidonine and the alkaloid extract inhibited P-gp/MDR1 activity in a concentration-dependent manner in Caco-2 and CEM/ADR5000 and reversed their doxorubicin resistance. In addition, chelidonine and the alkaloid extract inhibited the activity of the drug, modifying enzymes CYP3A4 and GST in a dose-dependent manner. The expression analysis identified a common set of regulated genes related to apoptosis, cell-cycle, and drug metabolism.
Results suggest that chelidonine is a promising compound for overcoming MDR and enhancing cytotoxicity of chemotherapeutics, especially against leukemia cells. Its efficacy needs to be confirmed in animal models (El-Readi, Eid, Ashour, Tahrani & Wink, 2013).
Induces Apoptosis, Leukemia
Sanguinarine, chelerythrine and chelidonine possess prominent apoptotic effects towards cancer cells. This study found that sanguinarine and chelerythrine induced apoptosis in human CEM T-leukemia cells, accompanied by an early increase in cytosolic cytochrome C that precedes caspases-8, -9 and -3 processing. Effects of sanguinarine and chelerythrine on mitochondria were confirmed by clear changes in morphology (3h), howerver chelidonine did not affect mitochondrial integrity. Sanguinarine and chelerythrine also caused marked DNA damage in cells after 1h, but a more significant increase in impaired cells occurred after 6h. Chelidonine induced intensive DNA damage in 15–20% cells after 24h.
Results demonstrated that rapid cytochrome C release in CEM T-leukemia cells exposed to sanguinarine or chelerythrine was not accompanied by changes in Bax, Bcl-2 and Bcl-X((L/S)) proteins in the mitochondrial fraction, and preceded activation of the initiator caspase-8 (Kaminskyy, Kulachkovskyy, & Stoika, 2008).
Induces Apoptosis
Chelerythrine, formerly identified as a protein kinase C inhibitor, has also been shown to inhibit the anti-apoptotic Bcl-2 family proteins. Chelerythrine initiates the rapid mitochondrial apoptotic death of H9c2 cardiomyoblastoma cells in a manner that is likely independent of the generation of ROS from mitochondria (Funakoshi et al., 2011).
Oral Cancer, Inhibits cell proliferation
The effects of benzo[c] phenanthridine alkaloids (QBA), known mainly as sanguinarine and chelerythrine, on the inhibition of some kinds of cancer cell proliferation have been established. Sanguinarine is a potential inhibitor of tumorigenesis which suggests that it may be valuable in the development of new anti-cancer drugs for the treatment of oral squamous cell carcinoma (OSCC) (Tsukamoto et al., 2011).
Apoptotic Effects; Melanoma
Mixtures of isoquinoline alkaloids containing protopine, chelidonine, sanguinarine, allocryptopine, and stylopine were applied to murine fibroblast NIH/3T3, mouse melanoma B16F10, and human breast cancer MCF7 cell cultures for 20 and 40 min, and the content of alkaloids in the cell media was measured by capillary electrophoresis (CE). CE separation of isoquinoline alkaloids was performed in 30 mM phosphate buffer (pH 2.5). As these alkaloids have native fluorescence, they were directly detected using the commercially available UV light-emitting diode without fluorescent derivatization. The results showed a differential ability of celandine alkaloids to penetrate into the normal and cancer cell interior, which was inversely proportional to their cytotoxic activity.
While the most effective transport of celandine alkaloids from the cell medium to the cell interior was observed for normal murine fibroblast NIH/3T3 cells (about 55% of total content), cytotoxicity tests demonstrated selective and profound apoptotic effects of a five-alkaloid combination in the mouse melanoma B16F10 cell line (Kulp & Bragina, 2013).
Leukemia
The methanol extract isolated from the greater celandine Chelidonium majus L. (CME) has a strong anti-oxidant potential and exerted the anti-proliferative activity via apoptosis on leukemia cells. CME, due to the presence of the isoquinoline alkaloids and the flavonoid components may play an important role in both cancer chemoprevention through its anti-oxidant activity and modern cancer chemotherapy as a cytotoxic and apoptosis-inducing agent (Nadova et al., 2008).
Apoptosis-inducing Activity
Apoptogenic and DNA-damaging effects of chelidonine (CHE) and sanguinarine (SAN), two structurally related benzophenanthridine alkaloids isolated from Chelidonium majus L. (Papaveraceae), were compared. Both alkaloids induced apoptosis in human acute T-lymphoblastic leukaemia MT-4 cells. Apoptosis induction by CHE and SAN in these cells was accompanied by caspase-9 and -3 activation and an increase in the pro-apoptotic Bax protein. An elevation in the percentage of MT-4 cells possessing caspase-3 in active form after their treatment with CHE or SAN was in parallel to a corresponding increase in the fraction of apoptotic cells. CHE, in contrast to SAN, does not interact directly with DNA.
This fact is in line with DNA-damaging effects of the alkaloids detected in the COMET assay. Nevertheless, apoptosis-inducing activity of CHE even slightly exceeded that of SAN (Philchenkov et al., 2008).
Chelidonium majus L. alkaloids chelidonine, sanguinarine, chelerythrine, protopine and allocryptopine were identified as major components of Ukrain. Apart from sanguinarine and chelerythrine, chelidonine turned out to be a potent inducer of apoptosis, triggering cell death at concentrations of 0.001 mM, while protopine and allocryptopine were less effective. Similar to Ukrain, apoptosis signaling of chelidonine involved Bcl-2 controlled mitochondrial alterations and caspase-activation (Habermehl et al., 2006).
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