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Investigational New Drugs

, Volume 32, Issue 5, pp 806–814 | Cite as

In vitro 3D colon tumor penetrability of SRJ09, a new anti-cancer andrographolide analog

  • Charng Choon Wong
  • Nagarajan Periasamy
  • Sreenivasa Rao Sagineedu
  • Shiran Sidik
  • Shariful Hasan Sumon
  • Paul Loadman
  • Roger Phillips
  • Nordin Haji Lajis
  • Johnson StanslasEmail author
PRECLINICAL STUDIES

Summary

Limited tumor penetrability of anti-cancer drugs is recognized as one of the major factors that lead to poor anti-tumor activity. SRJ09 (3,19-(2-bromobenzylidene) andrographolide) has been identified as a lead anti-cancer agent for colon cancer. Recently, this compound was shown by us to be a mutant K-Ras binder. In this present study, the penetrability of SRJ09 through the DLD-1 colon cancer multicell layer (MCL) was evaluated. The amount of SRJ09 that penetrated through the MCL was quantitated by utilizing high performance liquid chromatography (HPLC). Histopathological staining was used to visualize the morphology of MCL. A chemosensitivity assay was performed to assess the anti-cancer activity of SRJ09 in DLD-1 cells. SRJ09 was able to penetrate through DLD-1 MCL and is inversely proportional with the MCL thickness. The flow rates for SRJ09 through MCL were 0.90 ± 0.20 μM/min/cm2 and 0.56 ± 0.06 μM/min/cm2 for days 1 and 5, respectively, which are better than doxorubicin. Histopathological examination revealed that the integrity of the DLD-1 MCL was retained and no visible damage was inflicted on the cell membrane, confirming the penetration of SRJ09 was by diffusion. Short term exposure (1 h) in DLD-1 cells demonstrated SRJ09 had IC50 of 41 μM which was approximately 4-folds lower than andrographolide, the parent compound of SRJ09. In conclusion, SRJ09 successfully penetrated through DLD-1 MCL by diffusion and emerged as a potential candidate to be developed as a clinically viable anti-colon cancer drug.

Keywords

Andrographolide analogue Colon cancer Tumor penetration DLD-1 Multi cell layer 

Notes

Acknowledgments

The project was funded by the Research University Grant Scheme (RUGS) (Grant: 04-01-09-0713RU; 04-02-12-2017RU) through the Ministry of Higher Education. The European Association for Cancer Research (EACR) is thanked for providing a travel fellowship to Charng Choon Wong.

Conflict of interest

The authors state no conflict of interest.

Supplementary material

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Charng Choon Wong
    • 1
  • Nagarajan Periasamy
    • 2
  • Sreenivasa Rao Sagineedu
    • 3
    • 6
  • Shiran Sidik
    • 4
    • 7
  • Shariful Hasan Sumon
    • 5
  • Paul Loadman
    • 2
  • Roger Phillips
    • 2
  • Nordin Haji Lajis
    • 3
  • Johnson Stanslas
    • 1
    • 3
    Email author
  1. 1.Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health SciencesUniversiti Putra MalaysiaSerdangMalaysia
  2. 2.Institute of Cancer TherapeuticsUniversity of BradfordBradfordUnited Kingdom
  3. 3.Laboratory of Natural Products, Institute of BioscienceUniversiti Putra MalaysiaSerdangMalaysia
  4. 4.Histopathology Unit, Department of Pathology, Faculty of Medicine and Health SciencesUniversiti Putra MalaysiaSerdangMalaysia
  5. 5.Neurology Unit, Department of Medicine, Faculty of Medicine and Health SciencesUniversiti Putra MalaysiaSerdangMalaysia
  6. 6.Department of Pharmaceutical Chemistry, School of PharmacyInternational Medical UniversityKuala LumpurMalaysia
  7. 7.Perdana University-Royal College of Surgeons in Ireland (PU-RCSI), School of Medicine, Perdana UniversitySerdangMalaysia

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