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Karwinskia humboldtiana |
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Adame-Reyna M., M. Guerrero-Olazarán, R. Belmontes-Hernández and J. M. Viader-Salvadó. 1994. [Pharmacokinetic design for the preclinical phase. Application to the study of an anthracenone] Rev Invest Clin. 46(1):53-8. “T-514 is a toxic substance of Karwinskia humboldtiana which has been described as a possible anticancer agent. An animal model (New Zeland white rabbit) was selected for pharmacokinetic studies that would allow the performance of surgical techniques to catheterize central vessels in order to obtain blood samples at short time intervals. A nonlinear regression analysis method was used to fit the plasmatic concentration data to a multiexponential mathematical function; a computer program based on Marquant's iterating algorithm was used to fit the experimental curves. In the present work we show the advantage of introducing two catheters of different diameters in the jugular vein using modifications of the Seldinger and Braunüle techniques: a catheter of small diameter (18 G) is used to introduce the drug and a larger one (16 G) to sample at different times. The larger diameter catheter facilitates a rapid sampling of blood (two mL/s) which is essential to determine the initial phase of the distribution process (alpha phase). The behavior of T-514 corresponded to a two-compartment model with a biexponential equation C = 0.35 e-0.13(t-2) + 0.17 e-0.03(t-2).” Caballero-Quintero A., A. Piñeyro-López and N. Waksman. 2001. In vitro binding studies of the peroxisomicine A1-BSA and -HSA interactions. Int. J. Pharm. 229 (1-2): 23–28. “Peroxisomicine A1 (PA1) is a dimeric hydroxyanthracenone isolated from fruits of plants belonging to the genus Karwinskia. Showing selective toxicity between malignant and benign cell lines, it is currently under screening as an antineoplastic agent. Very little is known about its mechanism of action. In the present work the extent of binding of this substance with Bovine Serum Albumin (BSA) and Human Serum Albumin (HSA) at pH 7.2 and 7.4 has been evaluated using the spectrophotometric method. Absorbance of PA1 was altered by the presence of albumin and this property was used to generate binding isotherms. The investigation was carried out at four different temperatures. The data were analyzed by assuming two types of binding sites. Results indicated that PA1 binds to both albumins at physiological pH, which is reflected by the affinity constants of the order of 10(5). There are two types of binding sites in the albumin for PA1; with the electrostatic forces being discarded, the hydrophobic and hydrogen bond are more probable. Binding with HSA is stronger than with BSA.” Galindo V.R. and N. Waksman. 2001. Cytotoxic hydroxyanthracenones from fruits of Karwinskia parvifolia. Nat. Prod. Lett. 15(4): 243–251. “Peroxisomicines A1 (1) and A2 (2) are cytotoxic hydroxyanthracenones isolated from the fruits of Karwinskia parvifolia. Peroxisomicine A1 exhibits selective cytotoxicity against several tumor cell lines. In the present investigation three minor constituents were obtained from the same fruit extracts: peroxisomicine A3 (3) and isoperoxisomicines A1 (4) and A2 (5). Compounds 3 and 5 are novel and their structures were determined by spectroscopic methods and molecular modeling. Compounds 1-5 were significantly cytotoxic against hepatoma cell lines.” Henselová M. and D. Hudecová. 2001. Differences in the microflora of scarified and unscarified seeds of Karwinskia humboldtiana (Rhamnaceae). Folia Microbiol (Praha).46(6): 543–548. “Seeds of Karwinskia humboldtiana obtained from a 1997 collection in the locality of Villa de Gracía Nuevo (León, Mexico) were contaminated with spores of filamentous fungi, bacteria and yeasts. The concentration of microorganisms in unscarified seeds ranged from 3.0 x 10(3) to 7.5 x 10(3) CFU/g. Predominant were bacterial isolates of the genera Aeromonas sp., Bacillus, and Pseudomonas; from filamentous fungi were identified Alternaria, Aspergillus niger, Cladosporium sp., Fusarium sp., Mucor sp., Penicillium commune, Trichothecium sp.; from yeasts Rhodotorula sp. and Saccharomyces cerevisiae. Seed scarification significantly reduced the microbial contamination. Of the original fungal isolates, only two were identified on scarified seeds, viz. Cladosporium sp. and Saccharomyces cerevisiae; although a relatively high incidence of a unidentifiable of Penicillium sp. was found, the bacterial spectrum was not altered. Treatment of scarified seeds with Vitavax 200 WP and Pomarsol Forte 80 WP (3 mg/g seeds) augmented germination by 10-19% compared to treated unscarified seeds, and by 16-31% compared to untreated unscarified seeds.” Jaramillo-Juárez F., M. L. Rodríguez-Vázquez, J. Muñoz-Martínez, T. Quezada-Tristán, F. A. Posadas del Río, J. Llamas-Viramontes, A. Ortíz GG, Feria-Velasco and J. L. Reyes. 2005. The ATP levels in kidneys and blood are mainly decreased by acute ingestion of tullidora (Karwinskia humboldtiana). Toxicon. 46(1): 99–103. “Our previous acute toxicity studies with Karwinskia humboldtiana (Kh) in rats showed renal hemodynamic changes with a marked increase in the fractional excretion of sodium and morphological damage. To analyse the effects of Kh or 'tullidora' on energetic metabolism, a single dose of an oral preparation from the seed fruits was given to Wistar rats (1.25 g/kg). In tullidora-treated rats there was 8% mortality. ATP concentrations in renal tissue decreased significantly (control: 53.85+/-3.34, tullidora 38.28+/-5.31 micromol/g fresh tissue, P<0.05). Total blood (54.8+/-0.96, tullidora: 40.2+/-1.55 micromol/dL, P<0.01) and haemoglobin-ATP concentrations (3.69+/-0.12, tullidora: 2.56+/-0.11 micromol/g, P<0.01) were also significantly diminished. Moreover, the total protein in renal cortex from tullidora-treated rats decreased as compared to control group (control: 71.43+/-2.88, tullidora: 55.20+/-4.06 mg/g fresh tissue, P<0.05). In contrast, Na+-K+-ATPase activity in tullidora-treated animals was not different from control rats. These findings might partially explain the acute effects and mortality observed in the Kh treated rats.” Lansiaux A., W. Laine, B. Baldeyrou, C. Mahieu, N. Wattez, H. Vezin, F. J. Martinez, A. Piñeyro and C. Bailly. 2001. DNA topoisomerase II inhibition by peroxisomicine A(1) and its radical metabolite induces apoptotic cell death of HL-60 and HL-60/MX2 human leukemia cells. Chem. Res. Toxicol. 14(1):16–24. “Peroxisomicine A(1) (T-514) is a dimeric anthracenone first isolated from the plant Karwinskia humboldtiana. The compound presents a high and selective toxicity toward liver and skin cell cultures and is currently the subject of preclinical studies as an antitumor drug. To date, the molecular basis for its diverse biological effects remains poorly understood. To elucidate its mechanism of action, we studied its interaction with DNA and its effects on human DNA topoisomerases. Practically no interaction with DNA was detected. Peroxisomicine was found to inhibit topoisomerase II but not topoisomerase I. DNA relaxation and decatenation assays indicated that the drug interferes with the catalytic activity of topoisomerase II but does not stimulate DNA cleavage, in contrast to conventional topoisomerase poisons such as etoposide. Two human leukemia cell lines sensitive or resistant to mitoxantrone were used to assess the cytotoxicity of the toxin and its effect on the cell cycle. In both cases, peroxisomicine treatment was associated with a loss of cells from every phase of the cell cycle and was accompanied by a large increase in the sub-G1 region which is characteristic of apoptotic cells. The cell cycle changes were more pronounced with the sensitive HL-60 cells than with the resistant HL-60/MX2 cells (with reduced topoisomerase II activity), in agreement with the cytotoxicity measurements. Treatment of HL-60 cells with T-514 stimulated the cleavage of the poly(ADP-ribose) polymerase by intracellular proteases such as caspase-3. The cytometry and Western blot analyses reveal that peroxisomicine induces apoptosis in leukemia cells. In addition, we characterized a catabolite of peroxisomicine, named T-510R, in the form of a highly stable radical metabolite. The electron spin resonance and mass spectrometry data are consistent with the formation of an anionic semiquinonic radical. The oxidized product T-510R inhibits topoisomerase II with a reduced efficiency compared to the parent toxin and was found to be about 3-4 times less toxic to both the sensitive and resistant leukemia cell lines than T-514. Collectively, the results suggest that topoisomerase II inhibition plays a role in the cytotoxicity of the plant toxin peroxisomicine. Inhibition of topoisomerase II may serve as an inducing signal triggering the apoptotic cell death of leukemia cells exposed to the toxin. The dihydroxyanthracenone unit may represent a useful chemotype for the preparation of topoisomerase II-targeted anticancer agents.” Moreno-Sepúlveda M., R. Vargas-Zapata, D. Esquivel-Escobedo, N. Waksman de Torres and A. Piñeyro-López. 1995. Effect of peroxisomicine and related anthracenones on catalase activity. Planta Med. 61(4): 337–340. “Dimeric anthracenones were isolated from toxic plants of the genus Karwinskia (Rhamnaceae). T 514 or peroxisomicine A1 is one of these toxic compounds which produces an irreversible and selective damage on the peroxisomes of yeast cells in vivo. In this paper we now report the inhibitory effect in vitro of peroxisomicine A1 and other structurally related anthracenones on liver catalase activity. The peroxisomicine A1 produces a non-competitive inhibition with respect to H2O2 on bovine, dog, and mouse liver catalases. In the three cases Vmax was decreased whereas Km was unaffected. Other dimeric anthracenones of natural origin were also found to be inhibitors of bovine liver catalase. There is a relationship between structure and degree of inhibition of all anthracenonic compounds tested. Peroxisomicine A1 and peroxisomicine A2 caused the highest degree of inhibition (IC50 = 3.34 and 3.64 microM, respectively).” Nava M.E., J. L. Castellanos and M. E. Castañeda. 2000. [Geographical factors in the epidemiology of intoxication with Karwinskia (tullidora) in Mexico] Cad Saude Publica. 16(1): 255–260. “Consumption of fruits from the genus Karwinskia may cause a flaccid paralysis that can be confused with the Guillan-Barré syndrome or poliomyelitis. Paralysis resulting from consumption of such fruit has emerged as a public health problem in certain regions of Mexico. The purpose of this study was to investigate geographical factors associated with this intoxication in the 72 cases reported in Mexico from 1990 to 1994. Location of cases coincides with the distribution of the 11 reported species of Karwinskia in the country. The majority of reported cases were related to the consumption of K. humboldtiana, with a smaller number involving K. mollis, K. parvifolia, K. johnstonii, and K. rzedowskii. Most cases were located in regions with dry climates (79.2%), arid vegetation (41. 7%), and altitudes under 1,000 meters above sea level (54.1%). The study establishes three different risk areas: the Balsas river region in the southwestern central part of the country; the arid northern area; and the arid and dry central area. Cases were from rural communities with low levels of schooling and poor socioeconomic conditions.” Ocampo-Roosens L. V., P. G. Ontiveros-Nevares and O. Fernández-Lucio. 2007. Intoxication with buckthorn (Karwinskia humboldtiana): report of three siblings. Pediatr. Dev. Pathol. 10(1): 66–68. “A variety of plants and seeds, some of which are used for therapeutic and nutritional purposes, can cause neurotoxic symptoms. The ingestion of the green or ripe fruit of the Karwinskia humboldtiana (buckthorn), a bush known in Mexico as coyotillo or tullidora, causes a flaccid, symmetric, progressive, and ascending palsy of the lower limbs, which, in severe cases, can cause bulbar palsy and death. The neurologic symptoms are similar to those of poliomyelitis, Guillain-Barré syndrome, and other polyradiculoneuritis syndromes, for which it is often mistaken. The clinical diagnosis of intoxicated patients can be difficult without a history of the fruit ingestion. We present a report of three siblings with buckthorn intoxication.” Piñeyro-López A., L. Martínez de Villarreal L and R. González-Alanís. 1994. In vitro selective toxicity of toxin T-514 from Karwinskia humboldtiana (buckthorn) plant on various human tumor cell lines. Toxicology. 1994 Sep 6;92(1-3):217-27. “Toxin T-514 is a dimeric anthracenone isolated from the Karwinskia humboldtiana (buckthorn) plant. Its potential anti-neoplastic effect was evaluated in vitro and the results obtained were compared with the effect of other known anti-cancer agents. Normal and malignant continuous cell lines were tested. After a 72-h exposure, neoplastic cells derived from hepatic, pulmonary and colonic tissues were more sensitive to toxin T-514 than normal cells from the corresponding organ. Hepatoma cells and colon adenocarcinoma CT50 values were < 10 micrograms/ml. Lung adenocarcinoma, undifferentiated bronchogenic cancer cells and small cell carcinoma CT50 values were < 20 micrograms/ml. All benign cell CT50 levels tested were > 113 micrograms/ml. This in vitro selective toxicity found with toxin T-514 was also seen with 5-fluororacil and mitomycin for colon adenocarcinoma and with epidoxorubicin for undifferentiated bronchogenic cancer cells.” Salazar R., V. Rivas, G. González and N. Waksman. 2006. Antimicrobial activity of coupled hydroxyanthracenones isolated from plants of the genus Karwinskia. Fitoterapia. 77(5):398-400. “The in vitro activity of some isolated hydroxyanthracenones belonging to the genus Karwinskia against four bacteria, six filamentous fungi and four yeast are reported. These hydroxyanthracenones were found to possess antimicrobial activity, particularly against Streptococcus pyogenes, Candida albicans, C. boidinii, C. glabrata and Cryptococcus neoformans; minimal inhibitory concentrations range between 16 and 2 microg/ml.” Velazco M. R., R. Montero, E. Rojas, M. E. Gonsebatt, M. Sordo, A. Piñeyro and P. Ostrosky-Wegman. 1996. Genotoxic effects of Karwinskia humboldtiana toxin T-514 in peripheral blood lymphocytes. Anticancer Drugs 7(6): 710-715. “Toxicity by Karwinskia humboldtiana, a Rhamnaceae plant, has been assessed in a number of studies. Four dimmeric anthracenones, named T-496, T-514, T-516 and T-544 for their molecular weight, have been isolated from this plant. T-514, in particular, has been shown to be toxic to liver and lung as well as to tumoral cell lines, preferentially to those from liver tumors. For this reason it has been suggested that the toxin could be used as an antineoplastic agent. The present study was performed to characterize the biological activity of T-514 as a potential cytostatic and genotoxic agent. Peripheral blood lymphocytes in culture were used as a test system, where chromosomal aberrations and sister chromatid exchanges were scored in order to evaluate genotoxicity, and mitotic index and cell proliferation kinetics were used as parameters for cytostatic and cytotoxic ability. Genotoxicity to lymphocytes was negative. However, proliferation was affected by the toxin, demonstrating a cytostatic activity independent of genotoxic damage.” Waksman N., G. Benavides-Cortez and V. Rivas-Galindo. 1999. Biologically active anthracenones from roots of Karwinskia parvifolia. Phytochemistry 50(6):1041–1046. “Tullidinol, a neurotoxin isolated from fruits and roots of several Karwinskia species, was resolved for the first time into two stereoisomers. This was achieved by means of preparative HPLC from roots of Karwinskia parvifolia. Structural assignments were made on the basis of spectroscopic data, including long range correlations as well as geometry optimization by means of semi-empirical methods.”
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