Apoptosis inducing activity of 4-substituted coumarins from Calophyllum brasiliense in human leukaemia HL-60 cells

Abstract

With the objective of identifying anti-tumour-promoting agents, we carried out a primary screening of ten 4-substituted coumarins isolated from Calophyllum brasiliense Camb. (Guttiferae), to determine the ability of these compounds to inhibit proliferation of the human leukaemia cell line HL-60. Among the 4-substituted coumarins isolated, calophyllolide (2) and mammea B/BB (3) showed significant cytotoxicity against HL-60 cells. Fluorescence microscopy with Hoechst 33342 staining revealed that the percentage of apoptotic cells with fragmented nuclei and condensed chromatin increased in a time-dependent manner after treatment with calophyllolide (2) or mammea B/BB (3). In addition, the activity of caspase-9 and caspase-3 was also enhanced in a time-dependent manner upon treatment with the 4-substituted coumarins 2 and 3. Caspase-9 and caspase-3 inhibitors suppressed apoptosis induced by 4-substituted coumarins 2 and 3. These results suggest that calophyllolide (2) and mammea B/ BB (3) induced apoptosis in HL-60 cells through activation of the caspase-9/caspase-3 pathway, which is triggered by mitochondrial dysfunction.

Cytotoxic activity of Brazilian Cerrado plants used in traditional medicine against cancer cell lines

“…Several xanthones, coumarines, terpenoids and phenolic compounds were isolated from Calophyllum brasiliense with remarkable activities including anti-HIV (Huerta-Reyes et al, 2004), antibacterial (Pretto et al, 2004), trypanocidal (Abe et al, 2005), and anticancer against the cell lines KM-12 (colon adenocarcinome), U-251 (gliome), PC-3 (prostate), and K-562 and HL-60 (leukemias) (Reyes-Chilpa et al, 2004;Ito et al, 2006;Suffredini et al, 2007). Our results are in good agreement with those previously reported by Ito and collaborators concerning the anticancer activity in vitro against HL-60 cells of Calophyllum brasiliense.…”

Bioactive Coumarins and Xanthones From Calophyllum Genus and Analysis of Their Druglikeness and Toxicological Properties

“…They have shown to be active against several types of cancer cell lines, including PC3, HTC116, U251, and six human leukemic cell lines: BV173, K562, MALM6, HL60, SEM, and a P-glycoprotein over-expressing cell line). These compounds induced caspase-mediated cell death in most of these cells [50,51]. Interestingly, some of these coumarins (mammea A/BA, A/BB, B/BB) also have shown to be active against Trypanosoma cruzi and Leishmania amazonensis [52,53], inducing disruption of mitochondrial swelling and loss of normal ultrastructure in this parasite [28].…”

“…This research was supported by grant IN210016 from DGAPA-UNAM. concentration that increased the alkaline phosphatase LD 50 lethal doses 50 percent…”

Trends in the chemical and pharmacological research on the tropical trees Calophyllum brasiliense and Calophyllum inophyllum, a global context

“…In addition, 4-phenylcoumarins inophyllum A, C, D and E, three tricyclic coumarins such as calocoumarin A, B, and C, calofoloid, apetatolide, and phenolic cinnamic acid have also been isolated from the roots. Several xanthones such as inoxanthone, caloxanthone A and B, macluraxanthone, 1,5-dihydroxyxanthone, calophynic acid, brasiliensic acid, inophylloidic acid, calaustralin, calophyllolide, and inophyllum C and E have been isolated the leaves, as well as, friedelin-type triterpenoids, such ascanophyllol, canophyllic acid, friedelin, friedelan-3-one, 3,4-secofriedelane-3,28-dioic acid, 27-(acetyloxy) canophyllic acid, and 27-(acetyloxy)-3-oxofriedelan-28-oic acid (Ito et al 2006;Laure et al 2005).…”

“…3 the main biological research over the last years in C. brasiliense have been focused on its enviromental and ecological applications; for instance, it has been proposed the development of a phytomedicine (a extract from the leaves containing anti-HIV coumarins) as a strategy to impulse sustainable plantations, contributing to stop deforestation (César et al 2011;Tapia-Tapia and Reyes-Chilpa 2008). Even so, there is an important amount of papers for anti-parasitic activities, mostly related to mammea type coumarins, antileishmania (Brenzan et al 2007); and trypanocidal , as well as for cytotoxic properties specially against leukemia cell lines such as K562 and HL-60 (Ito et al 2006;Gomez-Verjan et al 2014;Kimura et al 2005), and antimicrobial properties mostly related to inhibition of Mycobacterium tuberculosis (Pires et al 2014) and Helicobacter pylori (Su et al 2008). This highlight C. brasiliense as a potential source of natural products, particulary mammea type coumarins with potential for the development of new drugs with antiparasite properties, and against leukemia.…”