APAG-1 DERIVATIVES AS ANTITUMOUR
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Apag 1 derivatives as antitumour agents

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.


Apag 1 derivatives as antitumour agents

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

Synthesis of APAG-1 Derivatives

APAG-1

SRJ01 SRJ04 SRJ05 SRJ06 - SRJ10

SRJ02 - SRJ03

condensation

condensation

acetylation

Heck reaction

acetylation


Apag 1 derivatives as antitumour agents

  • 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


Apag 1 derivatives as antitumour agents

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


Apag 1 derivatives as antitumour agents

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)


Apag 1 derivatives as antitumour agents

Figure 1. Mean graphs of APAG-1


Apag 1 derivatives as antitumour agents

Figure 2. Mean graphs of SRJ01


Apag 1 derivatives as antitumour agents

Figure 3. Mean graphs of SRJ03

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


Apag 1 derivatives as antitumour agents

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


Apag 1 derivatives as antitumour agents

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

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


Apag 1 derivatives as antitumour agents

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


Apag 1 derivatives as antitumour agents

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


Apag 1 derivatives as antitumour agents

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.


Apag 1 derivatives as antitumour agents

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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