Laurus nobilisL. Seed Extract Reveals Collateral Sensitivity in Multidrug-Resistant P-Glycoprotein-Expressing Tumor Cells

Abstract

The frequent failure of standard cancer chemotherapy requires the development of novel drugs capable of killing otherwise drug-resistant tumors. Here, we have investigated a chloroform extract of Laurus nobilis seeds. Fatty acids and 23 constituents of the volatile fraction were identified by gas chromotography/flame ionization detection (GC/FID) and gas chromatography/mass spectrometry (GC/MS), in good agreement with (1)H NMR (nuclear magnetic resonance) spectrum. Multidrug-resistant P-glycoprotein-expressing CEM/ADR5000 leukemia cells were hypersensitive (collaterally sensitive) toward this extract compared to drug-sensitive CCRF-CEM cells, whereas CEM/ADR5000 cells were 2586-fold resistant to doxorubicin as control drug. Collateral sensitivity was verified by measurement of apoptotic cells by flow cytometry. The log10IC50 values of 3 compounds in the extract (limonene, eucalyptol, oleic acid) did not correlate with mRNA expression of the P-glycoprotein-coding ABCB1/MDR1 gene and accumulation of the P-glycoprotein substrate rhodamine in the NCI panel of tumor cell lines. A microarray-based profile of 20 genes predicted resistance to doxorubicin and 7 other anticancer drugs involved in the multidrug resistance phenotype but not to limonene, eucalyptol and oleic acid. In conclusion, our results show that Laurus nobilis seed extract is suitable to kill multidrug-resistant P-glycoprotein expressing tumor cells.

Phytochemicals and Biological Activities of Laurel Tree (Laurus nobilis)

“…The anticancer activities of these extracts have driven the bioactivity-guided isolation of the responsible active compounds. Thus, lauroside B (76), a megastigmane glycoside from a methanolic extract of laurel leaves [211]; kaempferol-3-O-pcoumarate (134), a flavonoid from an ethyl acetate extract of laurel leaves [85]; costunolide (16), santamarine (28), reynosin (31), 11,13-dehydrosantonin (42), gazaniolide (45), spirafolide (48), and lauroxepine (65), sesquiterpenoids from a methanolic extract of laurel fruits [39]; anhydroperoxycostunolide (21) and 3-oxoeudesma-1,4(15),11(13)triene-12,6α-olide (43), sesquiterpenoids from a hot water extract of laurel leaves [94]; dehydrocostus lactone (22) and 3-chlorodehydrocostus lactone (25), sesquiterpenoids from a petroleum ether extract of laurel leaves [50]; costunolide (16), dehydrocostus lactone (22), 3-chlorodehydrocostus lactone (25), and lactone 49, sesquiterpenoids from a chloroform extract of laurel leaves [50,207]; lucentolide (20), anhydroperoxycostunolide (21), santamarine (28), reynosin (31), hydroperoxide-magnolialide (32), magnolialide (35), 3-peroxyarmefolin (36), 11,13dehydrosantonin (42), tubiferin (44), some more eudesmane lactones (30, 33, 34, 37, 38, 47), and several -hydroxyesters (60-64), all sesquiterpenoids from a dichloromethane extract of laurel leaves [52], have been isolated as the active compounds.…”

“…Dehydrocostus lactone (22), zaluzanin D (24) and eremanthin (26) were the first lactones isolated from laurel with a guaiane skeleton [38], and santamarine (28) and reynosin (31) the first ones with a eudesmane skeleton [40]. More guainolides (23,25,27) and eudesmanolides (29,30,(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47) were further isolated from both laurel fruits and leaves (Table 1). Lactone spirafolide (48), found in leaves [42,46] and fruits [39], has a rare molecular structure carrying an oxepine ring, and lactone 49 was a new sesquiterpene derivative [50].…”

“…In addition to this group of sesquiterpene lactones, which represent a characteristic group of phytochemicals in L. nobilis, other sesquiterpenoids have been isolated from methanol or chloroform extracts of laurel fruits [38,39] and leaves [41][42][43][44]47,[52][53][54] such as compounds 50-72 ( Figure 4). Eleven of all the sesquiterpenoids found in laurel tree were new natural products (25,27,29,49,50,52,58,(65)(66)(67)72) when isolated.…”

Laurus nobilis(laurel) aqueous leaf extract's toxicological and anti-tumor activities in HPV16-transgenic mice

“…4 Laurel is also rich in active substances with antibacterial, antifungal and antitumor properties. 5,6 In general, most antineoplastic drugs are associated with mild to severe side effects and their use is not always effective. So, there is a worldwide endeavor to discover new antineoplastic drugs from plants used in traditional medicine, which are more effective and more affordable and have fewer side effects.…”

Synthesis and in vitro biological evaluation of thiosulfinate derivatives for the treatment of human multidrug-resistant breast cancer

“…Phytochemicals have long been known to have numerous health benefits in addition to showing potential as anticancer agents and modulators of MDR [8][9][10] . Organosulfur compounds derived from Allium vegetables, such as onion (Allium cepa) and garlic (Allium sativum), are well documented as having a wide range of protective effects in numerous disease states.…”