Induction of apoptosis by lupeol in human epidermoid carcinoma A431 cells through regulation of mitochondrial, Akt/PKB and NF-kappaB signaling pathways

Abstract

The rising incidence of skin cancer in humans makes it equivalent to malignancies of organs. Therefore, it is necessary to intensify our efforts for better understanding and development of novel treatment and preventive approaches for skin cancer. Fruits and other plant derived products have gained considerable attention as they can reduce the risk of several cancer types. Lupeol, a triterpene, present in many fruits and medicinal plants, has been shown to possess many pharmacological properties including anti-cancer effect in both in vitro and in vivo assay systems. In the present study, apoptosis inducing effects of lupeol were studied in human epidermoid carcinoma A431 cells. Cell cycle analysis showed that lupeol treatment induces apoptosis (14-37%) in a dose-dependent manner as evident by an increased sub G(1) cell population. The RT-PCR and Western blot analysis showed that lupeol-induced apoptosis was associated with caspase dependent mitochondrial cell death pathway through activation of Bax, caspases, Apaf1, decrease in Bcl-2 expression and subsequent cleavage of PARP. Lupeol treatment also inhibited Akt/PKB signaling pathway by inhibition of Bad (Ser136) phosphorylation and 14-3-3 expression. In addition, lupeol treatment inhibited cell survival by inactivation of NFkappaB through upregulation of its inhibitor Ikappabetaalpha. The Caspase mediated apoptosis was noticed by decrease in lupeol induced apoptosis by Caspase inhibitors as well as increase in reactive oxygen species generation and loss of mitochondrial membrane potential. These results suggest that lupeol could be an effective anti-cancer agent and merits further investigation.

Modulating Effect of Lupeol on the Expression Pattern of Apoptotic Markers in 7, 12-Dimethylbenz(a)anthracene Induced Oral Carcinogenesis

“…Saleem et al (2008) pointed out that lupeol inhibited the growth of human metastatic melanoma cells in vitro and in vivo by up regulating Bax and caspase 3 and down regulating Bcl-2. Prasad et al (2009) reported that lupeol induced apoptosis in prostate cancer cells by up regulating Bax, caspase 3 and 9 and down regulating Bcl-2 genes. The present study are in line with other reported findings on apoptotic potential of lupeol.…”

Aegle marmelos (L.) Correa (Bael) and Its Phytochemicals in the Treatment and Prevention of Cancer

“…Lupeol, a triterpene, is shown to possess antineoplastic effects on various human neoplastic cell lines, for example, human melanoma 451Lu cells, 18 WM35 cells, 18 and B162F2 cells 19 ; human pancreatic adenocarcinoma cells AsPC-1 20 ; human epidermoid carcinoma A431 cells 21 ; hepatocellular carcinoma SMMC7721 cells 22 ; and prostate carcinoma cell lines LNCaP, 23 CWR22Rγ1, 23 and PC-3. 24 Its cytotoxicity was selective for neoplastic cells.…”

“…Activity-guided fractionation studies of the ethyl acetate fraction showed that the observed cytotoxic effects were primarily due to marmelin (discussed in detail in the next paragraph). 17 Additionally, experiments have also shown that the other phytochemicals such as lupeol, [18][19][20][21][22][23][24][25] eugenol, [26][27][28] citral, 29,30 cineole, 31 and d-limonene 31 present in Bael possess antineoplastic effects. In the following paragraphs, the antineoplastic effects of these phytochemicals are discussed in detail.…”

Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer

“…For example, Lupeol was shown to suppress cisplatin induced NF-jB activation and inhibited the orthotopically implanted head and neck squamous cell carcinoma in nude mice and skin cancer in CD-1 mice [134,135]. Lupeol has been shown to inhibit several pro-inflammatory mediators and oncogenic kinases pathways such as PI3K/AKT dependent pathway [136], and pro-inflammatory molecules such as prostaglandin E2/ TNF-a/IL-1b [137]. In addition, the beneficial and pre-clinical studies using lupeol has been recently reviewed [138].…”