Macrocyclic diterpenes resensitizing multidrug resistant phenotypes
- Bioorg Med Chem. 2014 Jul 15;22(14):3696-702. doi: 10.1016/j.bmc.2014.05.006.
- 1. Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
- 2. Charité Campus Mitte, Institute of Pathology, Berlin, Germany.
- 3. Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal. Electronic address: [email protected].
Herein, collateral sensitivity effect was exploited as a strategy to select effective compounds to overcome multidrug resistance in Cancer. Thus, eleven macrocyclic diterpenes, namely jolkinol D (1), isolated from Euphorbia piscatoria, and its derivatives (2-11) were evaluated for their activity on three different Human Cancer entities: gastric (EPG85-257), pancreatic (EPP85-181) and colon (HT-29) each with a variant selected for resistance to mitoxantrone (EPG85-257RN; EPP85-181RN; HT-29RN) and one to daunorubicin (EPG85-257RD; EPP85-181RD; HT-29RD). Jolkinol D (1) and most of its derivatives (2-11) exhibited significant collateral sensitivity effect towards the cell lines EPG85-257RN (associated with P-glycoprotein overexpression) and HT-29RD (altered Topoisomerase II expression). The benzoyl derivative, jolkinoate L (8) demonstrated ability to target different cellular contexts with concomitant high antiproliferative activity. These compounds were previously assessed as P-glycoprotein modulators, at non-cytotoxic doses, on MDR1-mouse lymphoma cells. A regression analysis between the antiproliferative activity presented herein and the previously assessed P-glycoprotein modulatory effect showed a strong relation between the compounds that presented both high P-glycoprotein modulation and cytotoxicity.