Selective in vitro anti-cancer activity of non-alkylating minor groove binders

Ryan Nichol, Abedawn Khalaf, Kartheek Sooda, Omar Hussain, Hollie Griffiths, Roger Phillips, Farideh Javid, C. J. Suckling, Simon Allison, Fraser Scott

Research output: Contribution to journalArticle

Abstract

Traditional cytotoxic agents which act through a DNA-alkylating mechanism are relatively non-specific, resulting in a small therapeutic window and thus limiting their effectiveness. In this study, we evaluate a panel of 24 non-alkylating minor groove binders (MGBs), including 14 novel compounds, for in vitro anti-cancer activity against a human colon carcinoma cell line, a cisplatin-sensitive ovarian cancer cell line and a cisplatin-resistant ovarian cancer cell line. A human non-cancerous retinal epithelial cell line was used to measure selectivity of any response. We have identified several MGBs with activities comparable to cis-platin and carboplatin, but with better in vitro selectivity indices, particularly MGB-4, MGB-74 and MGB-317. Moreover, a comparison of the cis-platin resistant and cis-platin sensitive ovarian cancer cell lines reveals that our MGBs do not show cross resistance with cisplatin or carboplatin and that they likely have a different mechanism of action. Finally, we present an initial investigation into the mechanism of action of one compound from this class, MGB-4, demonstrating that neither DNA double strand breaks nor the DNA damage stress sensor protein p53 are induced. This indicates that our MGBs are unlikely to act through an alkylating or DNA damage response mechanism.
LanguageEnglish
JournalMedicinal Chemistry Communications
Early online date18 Jul 2019
DOIs
Publication statusE-pub ahead of print - 18 Jul 2019

Fingerprint

Binders
Cell Line
Ovarian Neoplasms
Cisplatin
Carboplatin
Neoplasms
Cells
DNA Damage
DNA
Double-Stranded DNA Breaks
Cytotoxins
Heat-Shock Proteins
Colon
Epithelial Cells
In Vitro Techniques
Carcinoma
Sensors
Therapeutics
Proteins

Keywords

  • cytotoxic agents
  • minor groove binders (MGBs)
  • non-alkylating
  • in vitro anti-cancer activit

Cite this

Nichol, R., Khalaf, A., Sooda, K., Hussain, O., Griffiths, H., Phillips, R., ... Scott, F. (2019). Selective in vitro anti-cancer activity of non-alkylating minor groove binders.. https://doi.org/10.1039/C9MD00268E
Nichol, Ryan ; Khalaf, Abedawn ; Sooda, Kartheek ; Hussain, Omar ; Griffiths, Hollie ; Phillips, Roger ; Javid, Farideh ; Suckling, C. J. ; Allison, Simon ; Scott, Fraser. / Selective in vitro anti-cancer activity of non-alkylating minor groove binders. 2019.
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Nichol, R, Khalaf, A, Sooda, K, Hussain, O, Griffiths, H, Phillips, R, Javid, F, Suckling, CJ, Allison, S & Scott, F 2019, 'Selective in vitro anti-cancer activity of non-alkylating minor groove binders'. https://doi.org/10.1039/C9MD00268E

Selective in vitro anti-cancer activity of non-alkylating minor groove binders. / Nichol, Ryan; Khalaf, Abedawn; Sooda, Kartheek; Hussain, Omar; Griffiths, Hollie; Phillips, Roger; Javid, Farideh; Suckling, C. J.; Allison, Simon; Scott, Fraser.

18.07.2019.

Research output: Contribution to journalArticle

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T1 - Selective in vitro anti-cancer activity of non-alkylating minor groove binders

AU - Nichol, Ryan

AU - Khalaf, Abedawn

AU - Sooda, Kartheek

AU - Hussain, Omar

AU - Griffiths, Hollie

AU - Phillips, Roger

AU - Javid, Farideh

AU - Suckling, C. J.

AU - Allison, Simon

AU - Scott, Fraser

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Y1 - 2019/7/18

N2 - Traditional cytotoxic agents which act through a DNA-alkylating mechanism are relatively non-specific, resulting in a small therapeutic window and thus limiting their effectiveness. In this study, we evaluate a panel of 24 non-alkylating minor groove binders (MGBs), including 14 novel compounds, for in vitro anti-cancer activity against a human colon carcinoma cell line, a cisplatin-sensitive ovarian cancer cell line and a cisplatin-resistant ovarian cancer cell line. A human non-cancerous retinal epithelial cell line was used to measure selectivity of any response. We have identified several MGBs with activities comparable to cis-platin and carboplatin, but with better in vitro selectivity indices, particularly MGB-4, MGB-74 and MGB-317. Moreover, a comparison of the cis-platin resistant and cis-platin sensitive ovarian cancer cell lines reveals that our MGBs do not show cross resistance with cisplatin or carboplatin and that they likely have a different mechanism of action. Finally, we present an initial investigation into the mechanism of action of one compound from this class, MGB-4, demonstrating that neither DNA double strand breaks nor the DNA damage stress sensor protein p53 are induced. This indicates that our MGBs are unlikely to act through an alkylating or DNA damage response mechanism.

AB - Traditional cytotoxic agents which act through a DNA-alkylating mechanism are relatively non-specific, resulting in a small therapeutic window and thus limiting their effectiveness. In this study, we evaluate a panel of 24 non-alkylating minor groove binders (MGBs), including 14 novel compounds, for in vitro anti-cancer activity against a human colon carcinoma cell line, a cisplatin-sensitive ovarian cancer cell line and a cisplatin-resistant ovarian cancer cell line. A human non-cancerous retinal epithelial cell line was used to measure selectivity of any response. We have identified several MGBs with activities comparable to cis-platin and carboplatin, but with better in vitro selectivity indices, particularly MGB-4, MGB-74 and MGB-317. Moreover, a comparison of the cis-platin resistant and cis-platin sensitive ovarian cancer cell lines reveals that our MGBs do not show cross resistance with cisplatin or carboplatin and that they likely have a different mechanism of action. Finally, we present an initial investigation into the mechanism of action of one compound from this class, MGB-4, demonstrating that neither DNA double strand breaks nor the DNA damage stress sensor protein p53 are induced. This indicates that our MGBs are unlikely to act through an alkylating or DNA damage response mechanism.

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Nichol R, Khalaf A, Sooda K, Hussain O, Griffiths H, Phillips R et al. Selective in vitro anti-cancer activity of non-alkylating minor groove binders. 2019 Jul 18. https://doi.org/10.1039/C9MD00268E