Pinocembrin triggers Bax‐dependent mitochondrial apoptosis in colon cancer cells

Abstract

Bioflavanoids are the major pigments in plants with multitude of biological activities including inhibition of proliferation or induction of apoptosis in tumor cells. Even though the safety records of most flavanoids are exceptional, its therapeutic use is still in its infancy. We have isolated pinocembrin (5,7-dihydroxyflavanone) from Alpinia galanga that showed cytotoxicity against a variety of cancer cells including normal lung fibroblasts with relative nontoxicity to human umbilical cord endothelial cells. The compound induced loss of mitochondrial membrane potential with subsequent release of cytochrome c and processing of caspase-9 and -3 in colon cancer cell line HCT 116. Processing of caspase-8 was minimal. The initial trigger for mitochondrial apoptosis appears to be by the translocation of cytosolic Bax protein to mitochondria. Overexpression of proapoptotic Bax protein sensitized the colon cancer cells to pinocembrin-induced apoptosis and Bax knockout cells were resistant to pinocembrin-induced apoptosis. Antiapoptotic protein Bcl-X(L) only partially prevented apoptosis induced by this compound. The Bax-dependent cell death involving classical cytochrome c release and processing of caspase-9 and -3 suggests that pinocembrin is a classical mitochondrial apoptosis inducer. But the failure of Bcl-X(L) overexpression to completely prevent apoptosis induced by this compound suggests that pinocembrin is capable of triggering mitochondrial-independent cell death that needs to be clarified. The existence of cell death upon Bcl-X(L) overexpression is a promising feature of this compound that can be exploited against drug resistant forms of cancer cells either alone or in combination with other drugs.

Antiproliferative and apoptotic effects of pinocembrin in human prostate cancer cells

“…The rates of depletion of mitochondrial membrane potential were 84.02 ± 1.33% and 71.21 ± 1.74% in the cells treated with 100 and 150 µM of pinocembrin, respectively, for 24 h as compared to 96.12 ± 0.43% in the control group (Figure 6). These results are similar with previously reported studies in colon cancer (Kumar et al, 2007).…”

“…Furthermore, the cells become round-shaped and poorly adhered to the cultured plates while the control group cells showed a typical polygonal and cobblestone monolayer appearance and remained firmly attached to cultured plates (Figure 3). The results revealed that pinocembrin induced growth inhibition of LNCaP cells, in addition to other type of cancer cells previously reported including colon cancer (Kumar et al, 2007;Pan et al, 2011;Zizic et al, 2013) and leukemia (Hsu et al, 2010;Salahdeen and Murtala, 2012). …”

“…The results of flow cytometric analysis showed that rates of apoptosis were 19.21 ± 2.04% and 35.42 ± 2.27 % in the cells treated with 100 and 150 µM of pinocembrin respectively for 24 h as compared to 4.03 ± 0.47 % in the control cells (Figure 5). Pinocembrin (Kumar et al, 2007).…”

Pinocembrin, a major flavonoid in propolis, improves the biological functions of EPCs derived from rat bone marrow through the PI3K-eNOS-NO signaling pathway

“…3a); however, at doses higher than 50 mg/L, PIN inhibited EPC proliferation, which might be due to the fact that PIN at higher doses promote EPCs apoptosis (Kumar et al 2007). Similar dose-dependent effects of PIN on the migratory, adhesion and tube-forming abilities of EPCs were observed (Fig.…”

“…A recent study found that low-doses of PIN provide acute neurovascular protection in a glutamate injury model partly through the inhibition of p53 expression and cytochrome c release and by changing the Bax/Bcl2 ratio (Gao et al 2008). High doses of PIN induce mitochondrial apoptosis in a variety of cancer cells but are nontoxic to human umbilical cord endothelial cells (Kumar et al 2007). Our previous study found that PIN treatment significantly reduced atherosclerotic plaque area, plasma lipid levels, and increased the levels of plasma NO in apoE -/-mice fed a high-fat diet for 14 weeks.…”