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Aug 29, 2023Keywords:
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Cytotoxicity of Lupeol from the Stem Bark of Zanthoxylum gilletii against Multi-factorial Drug Resistant Cancer Cell Lines
Abstract
Background: Drug resistance is one of the major hurdles in the treatment of cancer. Rather than single factors, drug resistance is caused by multiple mechanisms making it even more complex. In the present study, the cytotoxicity of six compounds isolated from Zanthoxylum gilletii were screened against drug-sensitive leukemia CCRF-CEM cells. The most cytotoxic compound, lupeol (1) was further tested in a panel of nine human cancer cells, including multi-drug resistant phenotypes with different mechanisms and one normal cell line.
Methods: The structures of isolated compounds were characterized using spectroscopic techniques and comparison of their thin layer chromatography (TLC) profiles with authentic samples. The cytotoxicity tests were carried out using the resazurin reduction assay.
Results: In preliminary tests, all compounds except lupeol (1) were inactive at a fixed concentration of 40 µg/mL against drug-sensitive leukemia CCRF-CEM cells, as they displayed inhibition of <70% of the cell population. The IC50 values for lupeol (1) and doxorubicin were determined against a panel of cancer cell lines with drug-sensitive, multidrug-resistant (MDR) phenotypes and normal AML12 hepatocytes. Compound 1 displayed considerable cytotoxicity with IC50 values ranging from 13.60 µM (towards glioblastoma U87MG.ΔEGFR cells) to 69.39 µM (towards multidrug-resistant CEM/ADR5000 leukemia cells) and from 0.02 µM (towards CCRF-CEM cells) to 66.83 µM (towards the multidrug-resistant CEM/ADR5000 leukemia cells) for doxorubicin. Compound 1 showed higher toxicity to HepG2 liver carcinoma cells than to normal AML12 hepatocytes, indicating some degree of selectivity to tumor cells relative to normal cells. It is important to note that 1 exhibited collateral sensitivity against 3/5 cases, thus displaying its capacity to inhibit drug resistance cells through different mechanisms.
Conclusion: Lupeol (1) displayed interesting cytotoxic potencies against a panel of drug-sensitive and MDR tumor cells via multiple mechanisms with marginal or no effect to normal cells at similar doses.
