Synthesis, In Vitro and In Silico Analysis of New Oleanolic Acid and Lupeol Derivatives against Leukemia Cell Lines: Involvement of the NF-κB Pathway

Abstract

Oleanolic acid (OA) and Lupeol (LU) belong to the class of natural triterpenes and are endowed with a wide range of biological activities, including cytotoxicity toward several cancer cell lines. In this context, we investigated a set of compounds obtained from the two natural precursors for the cytotoxicity against leukemia HL60 cells and the multidrug-resistant (MDR) variant HL60R. Six new semi-synthetic triterpenes have been synthetized, fully characterized, and were investigated together with other triterpenes compounds for their pharmacological mechanism of action. The interaction of the more cytotoxic compounds with the nuclear factor kappa B (NF-κB) pathway has been also evaluated with the aid of docking. The lupane-like compounds were more active than the precursor, while the oleane-like compounds showed more complex behavior. Both OA and LU derivatives possess a similar interaction pattern with the p65 subunit of NF-kB, justifying the similar trend in their ability to inhibit the binding of p65 to DNA. Further, some of the derivatives tested were able to increase IκB-α levels preventing the translocation of NF-kB to the nucleus. In conclusion, this study offers a deeper insight on the pharmacological action of triterpenes toward leukemia cells, and it improves the background useful for the development of new anti-cancer drugs.

Anticancer potential of four triterpenoids against NCI-60 human tumor cell lines

“…Huang et al demonstrated cytotoxic effects of EK-2 against highly metastatic mouse melanoma cell (B16-BL6) and A549 (NSCLC), with IC 50 's of 10.8 µg/ml and 2.8 µg/ml, respectively [3]. Fontana et al demonstrated cytotoxic activities of oleanolic acid against HL-60 leukemia cell lines with IC 50 value of 44 µM [1]. Oleanolic acid differs from EK-8 with hydroxyl group at C-3 being β-oriented.…”

Natural Inhibitors of P-glycoprotein in Acute Myeloid Leukemia

“…Recently, Fontana et al [ 44 ] confirmed this mechanism of action in two AML cell lines, one of which was responsive and the other exhibited MDR. They showed that in the MDR cell line, the strong inhibition of NF-κB activation led to a reduction in P-gp expression.…”

The use of African medicinal plants in cancer management

“…Lupeol (LU) and Oleanolic acid (OA) are members of the class of natural triterpenes and possess wide-ranging biological activities and cytotoxicity against many cancer cell lines. From these two compounds, 6 novel semi-synthetic triterpenes were synthesized and studied for their pharmacological action ( Fontana et al, 2022 ). Compared to its precursor, Lupeol, the lupane-like compounds showed enhanced activity whereas the oleane-like compounds exhibited more complex properties.…”

“…The different OA and LU derivatives were investigated for their cytotoxic effects against acute myeloid leukemia cancer cell line HL60 as well as its multidrug-resistant (MDR) variant HL60R wherein the latter displayed multidrug resistance, P-gp overexpression, constitutive expression of the NF-κB transcription factor, inhibition of proteins associated with apoptosis and poor prognosis ( Fontana et al, 2022 ). These derivatives showed more activity than the original compounds and displayed equivalent cytotoxic effects against both HL60 and HL60R cell lines.…”