Collateral sensitivity of drug-resistant ABCB5- and mutation-activated EGFR overexpressing cells towards resveratrol due to modulation of SIRT1 expression

Mohamed E M Saeed, Muhammad Rahama, Victor Kuete, Mona Dawood, Mohamed Elbadawi, Yoshikazu Sugimoto, Thomas Efferth
Phytomedicine 2019 March 14, 59: 152890

BACKGROUND: In the drug discovery field, natural products deemed a precious source of novel lead compounds. They have the ability to bypass or overcome multidrug resistance (MDR) in cancer cells.

PURPOSE: In this study, the natural polyphenolic stilbene resveratrol (RES) has been studied for its cytotoxic activity toward MDR cancer cells.

METHODS: Resazurin assay was used to investigate the cytotoxicity of RES not only against a panel of drug-resistant cancer cells overexpressing P-glycoprotein/ABCB1, BCRP/ABCG2, ABCB5 (ATP-binding cassette transporters), but also mutation-activated EGFR. The assessment of proteins expression was done by Western blot analysis. COMPARE and hierarchical cluster analyses were applied to identify, which genes correlate with sensitivity or resistance to RES. The NF-κB activation was evaluated using NF-kB reporter cells assay.

RESULTS: Interestingly, MDR cells overexpressing ABCB5 and mutation-activated EGFR were collateral sensitive (CS) to RES. Our immunoblotting analysis highlighted that CS may be attributed to RES-induced sirtuin 1 (SIRT1) overexpression. Indeed, the SIRT1 inhibitor, sirtinol completely abolished CS to RES, indicating a causative role of SIRT1 for CS to RES. In addition, COMPARE and hierarchical cluster analyses of transcriptomic data indicated genes associated with diverse cellular mechanisms ranging from the immune response, inflammation signaling, and microtubule formation to cell migration. Searching for transcription factor binding motifs in the promoters of these genes pointed to NF-κB as one of the master regulators related to RES activity.

CONCLUSION: The findings demonstrate that RES alone or in combination with established chemotherapeutic agents might overcome the refractory tumors. This information may be immensely useful for the development of personalized treatment.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Trending Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"