Extracts of Indigenous Lebanese Plants as Source of Inhibitors of Tumor Proliferation and Metastasis

Résumé du livre

Metastasis is the most devastating aspect of cancer. The steps involved in the e stablishment of a metastatic focus involve a staircase progression from uncontro lled growth of neoplasms, to angiogenesis, decreased cohesiveness to neighboring cells and later, intravasation, adhesion in thin-walled capillaries and ultimat ely extravasation into secondary organs. Human T-cell leukemia virus type 1 is t he causative agent of an aggressively invasive hematological malignancy: Adult T -cell Leukemia/Lymphoma (ATL). This lethal disease is characterized by resistanc e to chemotherapy and extensive organ invasion. The ATL model fairly illustrates the stepwise progression of metastasis, with a noticeable focus on angiogenesis as a turning point in carcinogenesis. Clinical trials, including protocols rela tively tumor selective, have so far failed to cure ATL. We suggested a novel approach to ATL cure via indigenous Lebanese plant extracts . In fact, plants have been used for millennia as medicinal herbs. Recent studie s ascertain the molecular basis of their medicinal values. Their therapeutic imp ortance notably at metastatic stages, related to the presence of thousands of se condary metabolites, is reinforced by experimental trials of which Taxol stands up as a major illustration. Lebanon, one of the major countries known for its bi odiversity with its 2600 plant species, thus becomes an appealing ground for suc h research. The general aim of our study was to test for potential selective in vitro chemot herapeutic applications of the Lebanese plant, TF (crude and pure fractions) on leukemic cells, especially at the metastatically invasive stages. We used the en dothelial cell line ECV304 to rule out harmful effects on vascular linings, HTLV -1 negative (CEM - Jurkatt - Molt4) and positive (HuT-102 - MT2) cell lines, as well as normal activated lymphocytes. We first identified differential TF sensit ivity of cancer v/s. normal cells. We showed that up to 4 microgram/ml pure TF was mildly cytotoxic and largely in hibited leukemic cell proliferation in a dose-dependent manner, with increased s ensitivity of HTLV-1 negative cells. In mechanistic terms, pure TF induced a pre -G0 cell cycle arrest and a translational modulation of various cell-cycle regul ators (p53, p21, BAX/bcl-2 and cyclin D1). Besides, at 3 microgram/ml, TF ...