Berberine Berberine is an isoquinoline alkaloid present in the roots, rhizome and stem bark of a number of important medicinal plant species (e.g. Berberis aquifolium, Berberis vulgaris, Berberis aristata and Tinospora cordifolia etc.). The potential importance of berberine is indicated by its use in the Indian Ayurvedic (6), Unani and Chinese systems of medicine since time immemorial.
Berberine modulates AP-1 activity to suppress HPV transcription and downstream signaling to induce growth arrest and apoptosis in cervical cancer cells Sutapa Mahata1, Alok C Bharti1, Shirish Shukla1, Abhishek Tyagi1, Syed A Husain2 and Bhudev C Das13*
1 Division of Molecular Oncology, Institute of Cytology and Preventive Oncology (Indian Council of Medical Research), I-7, Sector-39, Noida, Gautam Budh Nagar - 201301 India 2 Department of Biosciences, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi -110025, India 3 Dr. B.R Ambedkar Centre for Biomedical Research, University of Delhi (North Campus), Delhi-110007, India
Background- Specific types of high risk Human papillomaviruses (HR-HPVs) particularly, HPV types 16 and 18 cause cervical cancer and while the two recently developed vaccines against these HPV types are prophylactic in nature, therapeutic options for treatment and management of already existing HPV infection are not available as yet. Because transcription factor, Activator Protein-1 (AP-1) plays a central role in HPV-mediated cervical carcinogenesis, we explored the possibility of its therapeutic targeting by berberine, a natural alkaloid derived from a medicinal plant species, Berberis which has been shown to possess anti-inflammatory and anti-cancer properties with no known toxicity; however, the effect of berberine against HPV has not been elucidated.
Results- We studied the effect of berberine on HPV16-positive cervical cancer cell line, SiHa and HPV18-positive cervical cancer cell line, HeLa using electrophoretic mobility gel shift assays, western and northern blotting which showed that berberine could selectively inhibit constitutively activated AP-1 in a dose- and time-dependent manner and downregulates HPV oncogenes expression. Inhibition of AP-1 was also accompanied by changes in the composition of their DNA-binding complex. Berberine specifically downregulated expression of oncogenic c-Fos which was also absent in the AP-1 binding complex. Treatment with berberine resulted in repression of E6 and E7 levels and concomitant increase in p53 and Rb expression in both cell types. Berberine also suppressed expression of telomerase protein, hTERT, which translated into growth inhibition of cervical cancer cells. Interestingly, a higher concentration of berberine was found to reduce the cell viability through mitochondria-mediated pathway and induce apoptosis by activating caspase-3.
Conclusion- These results indicate that berberine can effectively target both the host and viral factors responsible for development of cervical cancer through inhibition of AP-1 and blocking viral oncoproteins E6 and E7 expression. Inhibition of AP-1 activity by berberine may be one of the mechanisms responsible for the anti-HPV effect of berberine. We propose that berberine is a potentially promising compound for the treatment of cervical cancer infected with HPV.
Berberine inhibits growth, induces G1 arrest and apoptosis in human epidermoid carcinoma A431 cells by regulating Cdki–Cdk-cyclin cascade, disruption of mitochondrial membrane potential and cleavage of caspase 3 and PAR Sudheer K. Mantena1,Som D. Sharma1 andSantosh K. Katiyar1,2,3,*
Abstract Chemotherapeutic approach using non-toxic botanicals may be one of the strategies for the management of the skin cancers. Here we report that in vitro treatment of human epidermoid carcinoma A431 cells with berberine, a naturally occurring isoquinoline alkaloid, decreased cell viability (3–77%, P < 0.05–0.001) and induced cell death (3–51%, P < 0.01–0.001) in a dose (5–75 μM)- and time (12–72 h)-dependent manner, which was associated with an increase in G1 arrest. G0/G1 phase of the cell cycle is known to be controlled by cyclin dependent kinases (Cdk), cyclin kinase inhibitors (Cdki) and cyclins. Our western blot analysis showed that berberine-induced G1 cell cycle arrest was mediated through the increased expression of Cdki proteins (Cip1/p21 and Kip1/p27), a simultaneous decrease in Cdk2, Cdk4, Cdk6 and cyclins D1, D2 and E and enhanced binding of Cdki–Cdk. In additional studies, treatment of A431 cells with berberine (15–75 μM) for 72 h resulted in a significant dose-dependent increase in apoptosis (31–60%, P < 0.05–0.001) than non-berberine-treated control (11.7%), which was associated with an increased expression of pro-apoptotic protein Bax, decreased expression of anti-apoptotic proteins Bcl-2 and Bcl-xl, disruption of mitochondrial membrane potential, and activation of caspases 9, 3 and poly (ADP-ribose) polymerase. Pretreatment of A431 cells with the pan-caspase inhibitor (z-VAD-fmk) significantly blocked the berberine-induced apoptosis in A431 cells confirmed that berberine-induced apoptosis is mediated through activation of caspase 3-dependent pathway. Together, this study for the first time identified berberine as a chemotherapeutic agent against human epidermoid carcinoma A431 cells in vitro, further in vivo studies are required to determine whether berberine could be an effective chemotherapeutic agent for the management of non-melanoma skin cancers.
Introduction The risk of cancer is a growing health problem around the world particularly with the constantly rise in life expectancy, changes in environmental conditions, dietary habits and lifestyle. Among all the cancers, the incidence of non-melanoma skin cancers, including the squamous and basal cell carcinomas, represent the most common malignant neoplasms in humans, particularly in Caucasians. It has been estimated that ∼1.3 million new cases of skin cancers are diagnosed each year in the USA alone (1), which is equivalent to the incidence of malignancies in all other organs combined (2). According to current projections, one in five Americans will develop at least one non-melanoma skin cancer during their life-time. Thus cutaneous malignancies currently are a major burden on public health and healthcare expenditures. While not denying the importance of currently available sunscreens in the prevention of the risk of non-melanoma skin cancers, the use of sunscreens do not adequately protect the skin from the risk of cutaneous malignancies (3). Therefore, the development of effective chemopreventive or chemotherapeutic agents is required to address this issue.
There has been a considerable interest in the use of phytochemicals for the prevention of skin disorders including the risk of skin cancers. It has been noted that out of 121 prescription drugs in use for cancer treatment, 90 are derived from natural plant sources and ∼74% of these chemotherapeutic drugs were discovered by investigating a folklore claim (4,5). Berberine is an isoquinoline alkaloid present in the roots, rhizome and stem bark of a number of important medicinal plant species (e.g. Berberis aquifolium, Berberis vulgaris, Berberis aristata and Tinospora cordifolia etc.). The potential importance of berberine is indicated by its use in the Indian Ayurvedic (6), Unani and Chinese systems of medicine since time immemorial. Berberine possesses a wide range of biochemical and pharmacological activities, viz. antidiarrheal, antiarrhythmic and antitumor activities (7–10). Coptidis rhizoma, containing abundant berberine, is shown to inhibit the proliferation of esophageal cancer cells (11). Berberine inhibits cyclooxygenase-2 transcriptional activity in human colon cancer cells (10,12), and preliminary studies have shown that berberine sulfate inhibits tumor promoting activity of teleocidin in two-stage chemical carcinogenesis on mouse skin (13). Berberine also inhibits DNA topoisomerase I and II in biochemical system (14,15), and in fact, several classes of compounds that inhibit eukaryotic topoisomerase I or II have antitumor activity (16). Therefore, in an effort to develop an effective chemotherapeutic drug or agent for the prevention of non-melanoma skin cancers, we attempted for the first time to examine the chemotherapeutic effect of berberine on human epidermoid carcinoma A431 cells in in vitro system. We show that berberine inhibits the growth, proliferation and induces apoptosis in A431 cells. Our study also provides insight into the mechanism by which berberine induces apoptosis in these cells.