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APAG-1 DERIVATIVES AS ANTITUMOUR AGENTS

APAG-1 DERIVATIVES AS ANTITUMOUR AGENTS.

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APAG-1 DERIVATIVES AS ANTITUMOUR AGENTS

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  1. APAG-1 DERIVATIVES AS ANTITUMOUR AGENTS Srinivas R. Jada1,2, Johnson Stanslas1,2, Nordin H. Lajis2, Said Saad3, Ahmad S. Hamzah4, Andrew McCarroll5, Charlie Matthews5, Malcolm F.G. Stevens5, Faculty of Medicine and Health Sciences1/Institute of Bioscience2, Universiti Putra Malaysia1,2,3, 43400, Serdang, Selangor, Malaysia; Universiti Technology MARA4, Malaysia; Cancer Research Laboratories, University of Nottingham5, UK.

  2. Introduction APAG-1 is a diterpenoid lactone, isolated from a popular herb, found throughout Southeast Asia This herb is being used for the treatment of tonsillitis, bronchitis, pneumonia, cardiovascular and liver diseases APAG-1 possesses antitumour activity in in vitro and invivo breast cancer models1 In this study we synthesised novel derivatives of APAG-1 for evaluation of their antitumour properties

  3. Synthesis of APAG-1 Derivatives APAG-1 SRJ01 SRJ04 SRJ05 SRJ06 - SRJ10 SRJ02 - SRJ03 condensation condensation acetylation Heck reaction acetylation

  4. Results • In Vitro Antitumour Activities of APAG-1 and Its • Derivatives • Three Cell Line Prescreen • Only SRJ08 - 10 showed improved antitumour activity when compared with APAG-1 (Table 1) • SRJ01- 03 showed similar in activity as APAG-1 • SRJ04 - 06 displayed a reduced activity when compared with APAG-1 • SRJ07 failed to show activity

  5. Table 1. IC50* values for 11 compounds against 3 human cancer cell lines • *Determined using the 4-day MTT cytotoxic assay. Values are mean ± SD (n = 3) except for ** values are mean of n = 2. • Values are in µM • ND – not determined • MCF-7 – human breast cancer cells, H460 – non small lung cancer cells, PC3 – prostate cancer cells

  6. B. NCI 60 Cell Line Screen • The mean graphs (Figures 1, 2, 3) generated using the GI50, TGI and LC50 were used to determine tumour type selectivity by APAG-1 and its derivatives • The three compounds failed to exhibit a pronounced • antitumour selectivity • Among these 3 compounds, SRJ03 is most potent, followed by SRJ01 and APAG-1 (Table 2)

  7. Figure 1. Mean graphs of APAG-1

  8. Figure 2. Mean graphs of SRJ01

  9. Figure 3. Mean graphs of SRJ03 GI50 - 50% Growth Inhibition, TGI – Total Growth Inhibition, LC50 – 50% Lethal Concentration

  10. Table 2. Mean (±SD) GI50, TGI and LC50 values of APAG-1 and its derivatives in the NCI in vitro screen • Values are in µM

  11. Effect of APAG-1 and Its Derivatives on the Cell Cycle Progression of MCF-7 Cells • APAG-1: induced predominantly G1 and G2/M arrest at 24 hr time point and induced a S block at 48 hr and 96 hr time points (Table 3 and Figure 4) • SRJ01: overall this compound induced G1 and G2/M arrest • SRJ03: induced predominantly G2/M block at 24 hr and 48 hr time points and a S block at 96 hr time point • All the 3 compounds seem to induce apoptosis in MCF-7 cells indicated by the presence of apoptotic population (Pre- G1, Figure 4)

  12. Table 3. Summary of cell cycle results of APAG-1 and its derivatives • Numbers in bold indicate cell cycle arrest in that particular phase. ND : not determined. • Values are mean of n = 2

  13. Figure 4. DNA histograms of MCF-7 cells treated for 48 hours with APAG-1 and its derivatives G1 G1 7 M S G2 /M block G2 /M S Pre- G1 Pre- G1 G1 G1 7 M block G2 /M G2 /M S S Pre- G1 Pre- G1 G2 /M 5 M G1 G1 block G2 /M S Pre- G1 Pre- G1 S Pre – G1: Apoptotic population

  14. Conclusions • SRJ08, 09, 10 are more potent than APAG-1 • APAG-1 and its derivatives do not exhibit pronounced antitumour selectivity in the 60NCI cell lines • The in vitro antitumour activities of APAG-1 and its derivatives are not cell cycle specific • We are currently synthesising newer derivatives of APAG-1 to uncover agent(s) with increased antitumour potency and selectivity

  15. AcknowledgementsThe Ministry of Science, Technology and Environment of Malaysia (MOSTE) is thanked for funding this project under the IRPA grant 06-02-04-088. SRJ is grateful to European Association of Cancer Research (EACR) for providing Travel Fellowship award to carry out the preliminary synthesis work at the University of Nottingham.

  16. Reference1. Stanslas, J., Liew, P.S., Iftikhar, N., Lee, C.P., Saad, S., Lajis, N., Robins, R.A., Loadman, P., Bibby, M.C. 2001.Eur J cancer, 37 (suppl.6): 169.

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