Ent-Kaurene Analogs for Control of Colorectal Carcinoma Progression and Metastasis

Cancer is one of the leading causes of death in the world. In Hong Kong, colorectal carcinoma has led to the largest number of new cancer cases over the past four consecutive years and its incidence rate stays in an uprising trend. Irrespective of the type of cancer, most of the cancer deaths, accounting as much as 90%, are found in patients with metastasis. Multiple steps are required for cancer metastasis, which includes the transition of cancer cells from a sessile epithelial state to a mobile mesenchymal state. By undergoing the epithelial-mesenchymal transition (EMT), cancer cells become highly invasive. Therefore, the propensity of cancer for metastasis is positively correlated to the enhancement of EMT phenotypes, e.g. elevated migratory capacity and invasiveness, loss of E-cadherin, augmented production of extracellular matrix proteins and increased resistance to apoptosis. In this regard, chemotherapeutics targeting the EMT pathways are considered a rational strategy to suppress cancer progression and metastasis.

Ent-kauranes are a class of natural diterpenoid compounds abundantly found in the plants of Isodon genus (Lamiaceae family). For over 25 years, we have identified more than 70 ent-kaurane diterpenoids in 18 sub-structural groups from 16 different Isodon species. Some of them, especially compounds 5 and 12, displayed potent antitumor activity in our in vitro and in vivo experiments. We have recently found that this type of ent-kauranes exhibited pronounced growth inhibition in colorectal carcinoma cells, in which attenuated EMT phenotypes were also observed. Among them, those showing the highest anti-proliferative and anti-metastatic potential indeed possess the tetracyclic ent-kauranes with functional groups in ring C. Upon adequate structure-activity relationship (SAR) information, we will manipulate the ent-kaurane core with modification, addition and/or substitution of the active functional groups in order to improve the suppressive properties of the compounds on EMT events for control of cancer metastasis. As such, the general toxicity and associated side effects of our ent-kaurane analogs can be persuasively reduced. The long-term goal of this proposed study is to advance the ent-kaurane compounds as potential candidates amenable for the treatment of metastatic colorectal cancer. To achieve this goal, we propose to:
1) To synthesize ent-kaurane analogs as anticancer agents for control of invasiveness and metastasis of colorectal cancer;
2) To elucidate the anti-invasiveness and anti-metastasis potency and to identify the anticancer target(s) of ent-kaurane compounds for treatment of malignant colorectal cancer;
3) To validate the antitumor and anti-metastatic efficacies of ent-kaurane compounds in vivo.

Ultimately, we believe the ent-kaurane analogs are effective EMT inhibitors to control cancer progression and metastasis whilst serving as a putative alternative to the mainstay antitumor molecules in overcoming chemotherapy resistance.