Evaluation of Vernonia cinerea (Vc) in the Treatment of Cancer
Glioma remains a deadly disease with no effective clinical management strategies. Studies proposed will potentially identify natural product inhibitors of Signal Transducer and Activator of Transcription (Stat)3 as drug leads for glioma and breast cancer therapy. The outcome of the studies could further impact glioma understanding in regarding to the role of abnormal Sta3 in this disease. Vernonia cinerea (Vc) has a long history of use as a traditional herbal remedy for cancer in Asia. Our preliminary data show Vc is a source of a new generation of Stat3 inhibitors as potential anticancer therapeutics. Our rationale is based on our data that novel hirsutinolides preferentially target glioblastoma multiforme (GBM) phenotype in part by inhibiting aberrant Stat3 activity. Specifically, hirsutinolide 6 isolated from Vernonia cinerea inhibited tumor necrosis factor alpha (TNF-a)-induced nuclear factor kappa (NF-k)B activity, and that hirsutinolides 6, 10, and 22 blocked pStat3 in glioma U251MG cells. Thus, we hypothesize that Vc-derived compounds suppress the glioma phenotype by modulating the IL-6/Stat3 axis and NFkB cross-talk. Further, this project’s products hold great promise as new anticancer drugs based on the novel concept of Stat3 inhibition that are derived from a traditional herbal remedy with no reported side effects.
Relevance to Health Disparities: This proposal reflects the missions of Office of Minority Health and Health Disparities (OMHHE) initiatives. US cancer health disparities represent a major public health concern. According to the NCI, minority populations have higher overall incidence rates than the overall population regardless of social economic status (SES). Abnormal Stat3 activity is prevalent in and promotes human cancers that are disproportionally high among minorities, such as triple-negative breast cancer and liver cancer. In addition, studies have shown that inhibitors of abnormal Stat3 function might be useful as novel anticancer therapeutics.
Minority women, such as African-American and Hawaiians remain at higher risk for triple-negative breast cancer, and survival rate from this disease is rather low. Thus, the Stat3 inhibitors identified here would be useful for those cancers. Further, glioma has lagged behind many cancers in terms of discoveries that impact the disease management and the well being of patients and will benefit from this study. Our objectives: 1. To re-isolate and characterize compounds 6, 10, and 22 from the whole Vernonia cinerea plant material; 2. To pursue studies that will evaluate their activities against glioma and breast cancer cell viability in order to identify and prioritize active agents. Top prioritized compounds will further be studied for effects on glioma cell cycle progression, apoptosis, and the mechanisms of inhibition of Stat3-dependent events, including effects on interleukin (IL)-6 induced Stat3 signaling and the crosstalk with nuclear factor (NF) kappa B (NF-kB).