Hypermonones A-I,New Polyprenylated Acylphloroglucinols from Hypericum monogynum with Multidrug Resistance Reversal Activity

Eleven biogenetically related polyprenylated acylphloroglucinols(PPAPs),including four novel skeletons(1-4)and five new com-pounds(5-9),were isolated from the flowers of Hypericum monogynum.Hypermonones A-D(1-4)represented the first example of a unique dilactone structure containing carbonyl bonded single 5-lactone and tricyclic γ-lactone moieties.Their structures were elucidated by NMR analysis,X-ray crystallography,and ECD calculations.Moreover,we revised the structure of hyperibrin B to hy perm on one I(9)via NMR an alysis,a qua ntum computational chemistry method,and hypothetic bios yn thetic con siderations.Three compounds(5,6,and 9)with significant MDR reversal activity(RF ranging from 61 to 223)were superior to the positive control verapamil(MCF-7/ADR,RF:53;HepG2/ADRz RF:124).Mechanism study for compound 5 indicated that this compound could inhibit the function of P-gp tran sport rather tha n its expressi on,and the possible recog nition mechanism betwee n compo und 5 and P-gp was predicted by molecular docking.

Multidrug Resistance P-glycoprotein Function of Bone Marrow Hematopoietic Cells and the ReversalAgent Effect

The multidrug resistance P-glycoprotein (P-gp) expression and func-tion in hematopoietic stem/progenitor cells were studied to investigate whether the inhibition of hematopoietic cell P-gp function by multidrug resistance reversal agent increases the cytotoxicity of chemotherapy drugs on the hematopoietic cells.The expression of P-gp on the surface of CD cells from healthy human marrow was examined by flow cytometry. The multidrug resistance reversal agent MS-209 was used to measure the effects of MS-209 on the Rhodamin-123 uptaking o fCD hematopoietic cells. By using methylcellulose semi-solid culture, normal human granulocyte-macrophage clonal formation unit (CFU-GM) was cultured. The changes in CFU-GM inhibitory rate caused by daunorubicin were determined in the presence or absence of MS-2O9. The results showed that the P-gp expression rate of bone marrow CDL cells was 13. 3 %. MS-209 obviously increased the Rhodamin-123 uptake of CD positive cells. The mean inhibitory rate of daunorubicin for CFU-GM was 29. 6 %, but it was increased to 43. 3 % in the presence of MS-209 with the difference being significant (P< 0. 05). It was concluded that hematopoietic cells expressed P-gp protein and possessed active function- MS-209could inhibit the membrane efflux pump and increase the cytotoxicity of chemotherapy drugs to the clonal growth of hematopoeitic stem cells, suggesting the side effects of these drugs on the hematopoietic system should be taken into consideration in the clinical use.

REVERSION OF MULTIDRUG RESISTANCE IN THE P-GLYCOPROTEIN POSITIVE BREAST CANCER CELL LINE(MCF-7/ADR) BY INTRODUCTION OF HAMMERHEAD RIBOZYME

A hammerhead ribozyme which site-specifically cleaved the GUC position in canon 880 of the mdr1 mRNA was designed. The target site was chosen between the two ATP binding sites, which may be important for the function of the P-Gp as an ATP-dependent pump. A DNA sequence encoding the ribozyme gene was then incorporated into a eukaryotic expression vector (pH Apr-1 neo) and transfected into the breast cancer cell line MCF-7/Adr, which is resistant to adriamycin and expresses the MDR phenotype. The ribozyme was stably expressed in the cell line by the RNA dot blotting assay. The result of Northern blot assay showed that the expressed ribozyme could decrease the level of mdrl mRNA expression by 83. 5 %; and the expressed ribozyme could inhibite the formation of p-glycoprotein detected by immuno- cy-tochemistry assay and could reduce the cell’s resistance to adrimycin; this means that the resistant cells were 1 000-fold more resistant than the parental cell line(MCF-7), whereas those cell clones that showed ribozyme expression were only 6-fold more resistant than the parental cell line. These results show that a potentially useful tool is at hand which may inactivate MDR1 mRNA and revert the multidrug resistance phenotype.

Anticancer and multidrug-resistance reversing potential of traditional medicinal plants and their bioactive compounds in leukemia cell lines

Multidrug resistance remains a serious clinical problem in the successful therapy of malignant diseases. It occurs in cultured tumor cell lines, as well as in human cancers. Therefore, it is critical to develop novel anticancer drugs with multidrug-resistance modulating potential to increase the survival rate of leukemia patients. Plant-derived natural products have been used for the treatment of various diseases for thousands of years. This review summarizes the anticancer and multidrug-resistance reversing properties of the extracts and bioactive compounds from traditional medicinal plants in different leukemia cell lines. Further mechanistic studies will pave the road to establish the anticancer potential of plant-derived natural compounds.

Self-targeting visualizable hyaluronate nanogel for synchronized intracellular release of doxorubicin and cisplatin in combating multidrug-resistant breast cancer

Multidrug-resistance(MDR)featuring complicated and poorly defined mechanisms is a major obstacle to the success of cancer chemotherapy in the clinic.Compound nanoparticles comprising multiple cytostatics with different mechanisms of action are commonly developed to tackle the multifaceted nature of clinical MDR.However,the different pharmacokinetics and release profiles of various drugs result in inconsistent drug internalization and suboptimal drug synergy at the tumor sites.In the present study,a type of self-targeting hyaluronate(HA)nanogels((CDDPH)^ANG/DOX)to reverse drug resistance through the synchronized pharmacokinetics,intratumoral distribution,and intracellular release of topoisomerase II inhibitor doxorubicin(DOX)and DNA-crosslinking agent cisplatin(CDDP)is developed.With prolonged circulation time and enhanced intratumoral accumulation in vivo,(CDDP)^HANG/DOX shows efficient drug delivery into the drug-resistant MCF-7/ADR breast cancer cells and enhanced antitumor activity.Besides,fluorescence imaging of DOX combined with the micro-computed tomography(micro-CT)imaging of CDDP facilitates the visualization of this combination tumor chemotherapy.With visualizable synchronized drug delivery,the self-targeting in situ crosslinked nanoplatform may hold good potential in future clinical therapy of advanced cancers.

Concise Total Synthesis of Dysoxylactam A and a Simplified Analog

A total synthesis of 17-membered macrocyclolipopeptide dysoxylactam A,a potent agent reversing P-glycoprotein(P-gp)-mediated multidrug resistance(MDR)in cancer cells,was developed from the starting material(S)-2-methylbutanal in a linear sequence of 12 steps with 23.2%overall yield.The key steps include proline-catalyzed asymmetric aldol reaction,Evans aldol reaction and Krische allylation to construct the multiple stereocenters containing fragment,and ring-closing metathesis to furnish the macrocycle.This total synthesis facilitates the preparation of large amount samples of dysoxylactam A and the side chain simplified derivatives for further biological tests and preliminary structure-activity relationship exploration.