Antiproliferative Properties of Labdane Diterpenoids from Croton sylvaticus Hochst against Drug Sensitive and Resistant Leukemia cell lines

Abstract

Background: Cancer treatment failure is majorly attributed to the emergency of multi-drug resistance of cancer cells towards most conventional drugs used in chemotherapy hence the need for more active principles with less side effective from natural sources.

Methods: Characterization of isolated compounds was achieved using NMR spectroscopy and comparison of acquired data with literature values. The antiproliferative properties were determined using resazurin reduction assay.

Results: Three labdane diterpenoids namely; 18-nor-labd-13(E)-ene-8α, 15-diol (1), labd-13(E)-ene-8α, 15-diol (2) and austroinulin (3) were isolated from the stem bark of Croton sylvaticus. The crude extract was active at 10 µg/mL with cell inhibition of 86.96±4.86 against drug sensitive CCRF-CEM and 77.57±2.84% against drug resistant CEM/ADR5000 leukemia cell lines. However, all the compounds displayed lower antiproliferative potencies as they exhibited cell inhibitions<70% of the cell population at 10 µM. The cell inhibition of doxorubicin, was 94.89±0.86% and 24.20±2.89% against CCRF-CEM and CEM/ADR5000 cells, respectively. From these observations, it is clear that CEM/ADR5000 are resistant to doxorubicin while the activities of the compounds were similar against the two cell lines. This could be attributed to the similarities in their skeletal structures. Furthermore, 1 and 3 were more active than doxorubicin against CEM/ADR5000 cells.

Conclusion: The labdane diterpenoids displayed low cytotoxicity against CCRF-CEM cells and CEM/ADR5000 as compared to the crude extract. Doxorubicin was inactive against CEM/ADR5000 cells. Furthermore, 1 and 3 were more active than doxorubicin against CEM/ADR5000 cells. These compounds could be modified to obtained analogues with improved activities against the drug resistant cells.