Berberine-induced anticancer activities in FaDu head and neck squamous cell carcinoma cells

Abstract

Abstract. In the present study, we investigated berberine-induced apoptosis and the signaling pathways underlying its activity in FaDu head and neck squamous cell carcinoma cells. Berberine did not affect the viability of primary human normal oral keratinocytes. In contrast, the cytotoxicity of berberine was significantly increased in FaDu cells stimulated with berberine for 24 h. Furthermore, berberine increased nuclear condensation and apoptosis rates in FaDu cells than those in untreated control cells. Berberine also induced the upregulation of apoptotic ligands, such as FasL and TNF-related apoptosis-inducing ligand, and triggered the activation of caspase-8, -7 and -3, and poly(ADP ribose) polymerase, characteristic of death receptor-dependent extrinsic apoptosis. Moreover, berberine activated the mitochondria-dependent apoptotic signaling pathway by upregulating pro-apoptotic factors, such as Bax, Bad, Apaf-1, and the active form of caspase-9, and downregulating anti-apoptotic factors, such as Bcl-2 and Bcl-xL. In addition, berberine increased the expression of the tumor suppressor p53 in FaDu cells. The pan-caspase inhibitor Z-VAD-fmk suppressed the activation of caspase-3 and prevented cytotoxicity in FaDu cells treated with berberine. Interestingly, berberine suppressed cell migration through downregulation of vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2, and MMP-9. Moreover, the phosphorylation of extracellular signal-regulated kinase (ERK1/2) and p38, components of the mitogen-activated protein kinase pathway that are associated with the expression of MMP and VEGF, was suppressed in FaDu cells treated with berberine for 24 h. Therefore, these data suggested that berberine exerted anticancer effects in FaDu cells through induction of apoptosis and suppression of migration. Berberine may have potential applications as a chemotherapeutic agent for the management of head and neck squamous carcinoma.

Recent Advances in Berberine Inspired Anticancer Approaches: From Drug Combination to Novel Formulation Technology and Derivatization

“…This is largely based on induction of mitochondrial dysfunction as shown by changes in mitochondrial permeability and/or membrane potential (∆ψm) and caspase-dependent cell death [28,35,39,57,61]. As a marker of apoptosis, genes and proteins which are known to induce apoptosis in cancer cells (Bax, Bak, Bad, Apaf-1; Fas, FasL and tumour necrosis factor-α (TNF-α)) are upregulated while those associated with cell survival (Bcl-2 and Bcl-xL, survivin) are suppressed [24,35,40,42,47,49,[55][56][57][58][59]61,63]. The strong link between induction of apoptosis and generation of intracellular reactive oxygen species (ROS) by berberine has further been shown [43,60,61,63].…”

“…All these data suggest that berberine has the potential to induce apoptosis through the extrinsic cell-surface signalling (Fas, FasL or TNF-α) and intrinsic mitochondrial-based apoptotic pathways. In the latter case, the role of poly (ADP-ribose) polymerase (PARP) activation in the mitochondrial-dependent caspase activation and cell death has been shown [35,39,40,63]. The cell cycle arrest that vary depending on cell-type is initiated by targeting key checkpoint kinase targets leading to a reduction of, for example, cyclin D1 and cyclin E for G1 phase arrest [30] or cyclin D1, cyclin E, Cdk2, and Cdk4 for G0/G1 phase arrest [59].…”

“…Yu et al [64] Melanoma B16 cells and U937 cells B16 cells (IC 100 < 1 µg/mL) much more sensitive than U937 cells (IC 100 < 100 µg/mL) U937 cells; apoptotic cell death in U937 and necrosis in NB16 cells Cytotoxic to cancer cells Letasiová et al [65] The mitogen-activated protein kinase pathway which has profound effect on cell growth regulation is involved in mediating the anticancer effect of berberine. Accordingly, suppression of extracellular signal-regulated kinase (ERK) 1/2 action was shown in cholangiocarcinoma cell lines [30]; the phosphorylation of ERK1/2 and p38 was suppressed in FaDu head and neck squamous cell carcinoma cells [35], or in human non-small-cell lung cancer (NSCLC) cells [49]. Activation of p38 MAPK and c-Jun N-terminal kinase (JNK) while suppressing Janus kinase-2 (JAK2) was noted in breast cancer cells [45].…”

“…Hence, inhibition of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) as a result of NF-kB suppression is a key feature of angiogenesis inhibition by berberine [26,54]. Through suppression of COX and related signalling, those protein mediators critically involved in cancer metastasis such as matrix metalloproteinase (MMP) and vascular endothelial growth factor (VEGF) have been shown to be suppressed by berberine in various experimental models of cancer metastasis [27,29,35,45,49,54]. The numerous other targets of berberine associated with its anticancer effects are shown in Table 1 and how such effects on these targets could be enhanced by various approaches are detailed further in the following sections.…”

Biological Activity of Silver Nanoparticles and Their Applications in Anticancer Therapy

“…Metal-based AgNPs, known as pro-oxidative in different cancer cell lines [36] including breast MCF-7 and lung A549 cells [37] and squamous carcinoma SCC-25 cells [12], have shown novel applications in photodynamic therapy [37,38]. The alkaloid berberine was tested on squamous carcinoma cells as an antiproliferative and pro-apoptotic agent alone [22,[39][40][41] or in combination with AgNPs that improved its anticancer properties [12]. The antimicrobial activity of AgNPs as aseptic or preservative agents has been known since decades, and they also serve for synthesis of novel nanomaterials with potential applications in regenerative medicine [5].…”