Abstract
The cell inhibition activities of several Annonaceous acetogenins, covering the three major structural classes of bis-adjacent, bis-non-adjacent, and single tetrahydrofuran (THF) ring compounds and their respective ketolactone rearrangement products, were tested in an in vitro disk diffusion assay against three murine (P388, PO3, and M17/Adr) and two human (H8 and H125) cancerous cell lines as well as a non-cancerous immortalized rat GI epithelial cell line (I18). The results demonstrate a dose-dependent inhibition of cancerous cell growth, while non-cancerous cell growth is not inhibited by the same dosages. All of the acetogenins, irrespective of their various structural types, inhibit the growth of adriamycin resistant tumor cells and non-resistant tumor cells at the same levels of potency. These results show that the Annonaceous acetogenins are an extremely potent class of compounds, and their inhibition of cell growth can be selective for cancerous cells and also effective for drug resistant cancer cells, while exhibiting only minimal toxicity to 'normal' non-cancerous cells.
Highlights
The potent biological activity of the Annonaceous acetogenins continues to encourage our examination of their anticancer effects in vitro, as well as in vivo
We report preliminary results which demonstrate the selectivity of this highly potent class of compounds for cell growth inhibition of cancerous versus normal cells and demonstrate, that this growth inhibition is unaffected by adriamycin drug resistance
A common form of multidrug resistance (MDR) has been characterized by an increased expression of a 170 kDa plasma membrane glycoprotein, which acts as a cellular 'pump' extruding the anticancer agents before they can accumulate in lethal concentrations within the MDR cell
Summary
The potent biological activity of the Annonaceous acetogenins continues to encourage our examination of their anticancer effects in vitro, as well as in vivo. Over 12 years have elapsed since Joland et al [8] reported uvaricin as a new, in vivo active, antitumor agent; since over 160 of these natural compounds have been reported, and all of these show significant biological activity [3,5,14]; yet, the acetogenins have undergone only minimal testing in animal cancer models. The Annonaceous acetogenins have a similar potential to become life-prolonging compounds, and their further examination in animal tumor models should be undertaken as soon as possible. A major problem with regard to modern cancer chemotherapy stems from the emergence of cancerous cells which have developed resistance to the common chemotherapeutic agents such as adriamycin, vincristine, taxol, etc. Two homologous intracellular ATP binding sites are common to such transporter proteins, and they are believed to require the energy of ATP cleavage to effect active efflux [4]
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