APAG-1 DERIVATIVES AS ANTITUMOUR
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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.


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


Synthesis of APAG-1 Derivatives

APAG-1

SRJ01 SRJ04 SRJ05 SRJ06 - SRJ10

SRJ02 - SRJ03

condensation

condensation

acetylation

Heck reaction

acetylation


  • 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


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


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)


Figure 1. Mean graphs of APAG-1


Figure 2. Mean graphs of SRJ01


Figure 3. Mean graphs of SRJ03

GI50 - 50% Growth Inhibition, TGI – Total Growth Inhibition, LC50 – 50% Lethal Concentration


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


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)


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


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


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


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.


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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