Abstract
Isorhynchophylline (Rhy) is an active pharmacological component of Uncaria rhynchophylla that has been reported previously to exert significant antihypertensive and neuroprotective effects. However, very little is known about its potential anti-cancer activities. This study was carried out to evaluate the anticancer effects of Rhy against various human carcinoma cell lines. We found that Rhy exhibited substantial cytotoxic effect against human hepatocellular carcinoma HepG2 cells when compared with other human carcinoma cell lines including those of lung, pancreas, prostate, head and neck, breast, multiple myeloma, brain and renal cell carcinoma. Rhy induced apoptosis as characterized by accumulation of cells in sub G1 phase; positive Annexin V binding; activation of caspase-8, -9, and -3; and cleavage of PARP (poly-ADP ribose polymerase). This effect of Rhy correlated with the down-regulation of various proteins that mediated cell proliferation, cell survival, metastasis, and angiogenesis. Moreover, cell proliferation, migration, and constitutive CXCR4 (C-X-C chemokine receptor type 4), MMP-9 (Matrix metallopeptidase-9), and MMP-2 expression were inhibited upon Rhy treatment. We further investigated the effect of Rhy on the oncogenic cell signaling cascades through phospho-kinase array profiling assay. Rhy was found to abrogate phospho-p38, ERK, JNK, CREB, c-Jun, Akt, and STAT3 signals, but interestingly enhanced phospho-p53 signal. Overall, our results indicate, for the first time, that Rhy could exert anticancer and anti-metastatic effects through regulation of multiple signaling cascades in hepatocellular carcinoma cells.
Highlights
Isorhynchophylline (Rhy) is one of the major oxindole alkaloids isolated from Uncaria rhynchophylla, which has already been extensively used for the treatment of asthma, cancer, cirrhosis, diabetes, hypertension, stroke and rheumatism in tropical regions, such as Southeast Asia, Africa and southeast America [1]
To examine the anti-tumor activity of Rhy, HepG2, A549, BxPC-3, Caki-1, Roswell Park Memoria lIn stitute medium (RPMI)-8226, 786-O, Du145, FaDu, H1299, MDA-MB-231, U266, H4, U87MG, T98G, LN18 and immortalized primary human fetal astrocytes (IM-PHFA) cells were treated with Rhy (0, 50, 100, 150, 200, or 300 μM) for 48 h, and cell viability was measured by MTT assay
We evaluated the effect of Rhy on the expression of CXCR4, matrix metalloproteinases (MMPs)-9, and MMP-2, proteins which play a critical role in tumor metastasis
Summary
Isorhynchophylline (Rhy) is one of the major oxindole alkaloids isolated from Uncaria rhynchophylla, which has already been extensively used for the treatment of asthma, cancer, cirrhosis, diabetes, hypertension, stroke and rheumatism in tropical regions, such as Southeast Asia, Africa and southeast America [1]. Rhy has been reported to exhibit anti-inflammatory activities in mouse microglial cells [4,5]. Plant-derived natural products as well as their semisynthetic and synthetic analogs contribute significantly to the process of development of novel anti-neoplastic agents [6,7]. That has been extensively analyzed for its anticancer effects was reported to induce pathological changes of heart tissue and exhibit cardiotoxicity through the modulation of the mitochondria-mediated apoptotic signaling pathway [13] Triptolide, a major active ingredient extracted from the widely used Chinese herb Tripterygium wilfordii Hook f. that has been extensively analyzed for its anticancer effects was reported to induce pathological changes of heart tissue and exhibit cardiotoxicity through the modulation of the mitochondria-mediated apoptotic signaling pathway [13]
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