Hematologic malignancies account for a substantial percentage of cancers worldwide, and the heterogeneity and biological characteristics of leukemias and lymphomas present unique therapeutic challenges. Although treatment options exist for most of these diseases, many types remain incurable and the emergence of drug resistance is pervasive. Thus, novel treatment approaches are essential to improve outcome. Nearly half of the agents used in cancer therapy today are either natural products or derivatives of natural products. The enormous chemical diversity in nature, coupled with millennia of biological selection, has generated a vast and underexplored reservoir of unique chemical structures with biologic activity. This review will describe the investigation and application of natural products derived from higher plants in the treatment of leukemia and lymphoma and the rationale behind these efforts. In addition to the approved vinca alkaloids and the epipodophyllotoxin derivatives, a number of other plant compounds have shown promise in clinical trials and in preclinical investigations. In particular, we will focus on the discovery and biological evaluation of the plant-derived agent silvestrol, which shows potential for additional development as a new therapeutic agent for B-cell malignancies including chronic lymphocytic leukemia.
Four new flavanones, designated as
(+)−5″-deacetylpurpurin (1),
(+)−5-methoxypurpurin (2),
(2S)-2,3-dihydrotephroglabrin (3), and
(2S)-2,3-dihydrotephroapollin C (4), together
with two known flavanones (5 and 6), three known
rotenoids (7–9), and one known chalcone (10)
were isolated from a chloroform-soluble partition of a methanol extract from the
combined flowers, fruits, leaves, and twigs of Indigofera
spicata, collected in Vietnam. The compounds were obtained by
bioactivity-guided isolation using HT-29 human colon cancer, 697 human acute
lymphoblastic leukemia, and Raji human Burkitt’s lymphoma cell lines.
The structures of 1–4 were established by
extensive 1D- and 2D-NMR experiments and the absolute configurations were
determined by the measurement of specific rotations and CD spectra. The
cytotoxic activities of the isolated compounds were tested against the HT-29,
697, Raji and the CCD-112CoN human normal colon cells. Also, the quinone
reductase induction activities of the isolates were determined using the Hepa
1c1c7 murine hepatoma cell line. In addition,
cis-6aβ−12aβ-hydroxyrotenone
(7) was evaluated in an in vivo hollow fiber bioassay using
HT-29, MCF-7 human breast cancer, and MDA-MB-435 human melanoma cells.
Caeruleanone A, a Rotenoid with a New Arrangement of the D-Ring from the Fruits of Millettia caerulea. -(BUENO PEREZ, L.; PAN, L.; MUNOZ ACUNA, U.; LI, J.; CHAI, H.-B.; GALLUCCI, J. C.; NINH, T. N.; CARCACHE DE BLANCO, E. J.; SOEJARTO, D. D.; KINGHORN*, A. D.; Org. Lett. 16 (2014) 5, 1462-1465, http://dx.doi.org/10.1021/ol500266z ; Div. Med. Chem. Pharmacogn., Coll. Pharm., Ohio State Univ., Columbus, OH 43210, USA; Eng.) -U. Scheffler 34-214
Higher plants continue to afford humankind with many new drugs, for a variety of disease types. In this review, recent phytochemical and biological progress is presented for part of a collaborative multi-institutional project directed towards the discovery of new antitumor agents. The specific focus is on bioactive natural products isolated and characterized structurally from tropical plants collected in Vietnam. The plant collection, identification, and processing steps are described, and the natural products isolated from these species are summarized with their biological activities.
The potentiating action of the flavonolignan, (-)-hydnocarpin, in combination with vincristine was evaluated in the 697 acute lymphoblastic leukemia cell line and a P-gp-expressing variant, 697-R. Vincristine at 3 nM caused nearly complete growth inhibition in 697 cells, versus a 17% growth inhibition in 697-R cells. When combined with (-)-hydnocarpin at concentrations of 10 and 5 µM, vincristine-mediated growth inhibition in the 697-R cells increased significantly over the sum of the individual agents to 72% (p ≤ 0.0001), and 41% (p = 0.0256), respectively. Vincristine at 1.5 nM (66% growth inhibition) and 0.75 nM (39% growth inhibition) combined with (-)-hydnocarpin at 10 µM (42% growth inhibition) in the 697 cells, caused a significant increase in growth inhibition to 83% (p = 0.03) and to 61% (p < 0.0001), respectively, when compared to vincristine treatment as a single agent. To investigate the mechanism for the vincristine re-sensitization caused by (-)-hydnocarpin, the P-gp inhibitory effect of (-)-hydnocarpin was evaluated.
Caeruleanone A (1), a novel rotenoid with an unprecedented
arrangement of the D-ring, was isolated with another two new analogues,
caeruleanones B (2) and C (3), together
with 11 known rotenoids from the fruits of Millettia caerulea. The structures of the new compounds were determined by spectroscopic
data analysis, with that of 1 being confirmed by single-crystal
X-ray diffraction. Compounds 2 and 3 displayed
potent mitochondrial transmembrane potential inhibitory and quinone
reductase induction activities.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.