20(S)-Protopanaxadiol (PPD) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs

Liu, Junhua; Wang, Xu; Liu, Peng; Deng, Rongxin; Lei, Min; Chen, Wantao; Hu, Lihong

doi:10.1016/j.bmc.2013.04.067

Cited by 19 publications

(16 citation statements)

References 27 publications

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“…Ginsenoside Rg3 has been observed to compete with anticancer drugs for binding to ABCB1, thereby competitively inhibits drug efflux [ 18 ]. Derived from Rg3, 20( S )-protopanaxadiol (aPPD) and its analogues have also been reported to show reversal nature of ABCB1 inhibition [ 19 , 20 ]. Most ginsenosides share a dammarane-type triterpenoid saponin structure, while some minor ginsenosides isolated from P. quinquefolius with a modified steroid skeleton belong to ocotillol-type triterpenoids, of which the carbon chain at 20-position is replaced by a tetrahydrofuran ring [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Semi-synthetic ocotillol analogues as selective ABCB1-mediated drug resistance reversal agents

Zhang

et al. 2015

Oncotarget

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Overexpression of ATP-Binding Cassette transporters leads to multidrug resistance in cancer cells and results in the failure of chemotherapy. In this in-vitro study, we investigated whether or not (20S, 24R/S)-epoxy-12β, 25-dihydroxy-dommarane-3β-amine (ORA and OSA), a pair of semi-synthetic ocotillol analogue epimers, could inhibit the ABCB1 transporter. ORA (1 μM and 3 μM) significantly reversed the resistance to paclitaxel and vincristine in ABCB1-overexpressing SW620/Ad300 and HEK/ABCB1 cells, whereas OSA had no significant effects. In addition, ORA (3 μM) significantly increased the intracellular accumulation of [3H]-paclitaxel by suppressing the efflux function of ABCB1. Meanwhile, both ORA (3 μM) and OSA (3 μM) did not significantly alter the expression level or the subcellular location of ABCB1 protein. Moreover, the ABCB1 ATPase study suggested that ORA had a stronger stimulatory effect on the ATPase activity than OSA. ORA also exhibited a higher docking score as compared with OSA inside transmembrane domain of ABCB1. Overall, we concluded that ORA reverse ABCB1-mediated MDR by competitively inhibiting the ABCB1 drug efflux function.

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Section: Introductionmentioning

confidence: 99%

Semi-synthetic ocotillol analogues as selective ABCB1-mediated drug resistance reversal agents

Zhang

et al. 2015

Oncotarget

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“…Recently, PPD and its analogs have also been reported for their significant cancer cell growth inhibitory effects on human lung adenocarcinoma and oral squamous cell carcinoma. However, previous PPD studies focused on in vitro evaluations (23, 24). This study confirmed the anti-CRC effects of PPD in a dose-related manner using an in vivo xenograft nude mice model.…”

Section: Discussionmentioning

confidence: 99%

TRAIL pathway is associated with inhibition of colon cancer by protopanaxadiol

Zhang

et al. 2015

Journal of Pharmacological Sciences

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Among important components of American ginseng, protopanaxadiol (PPD) showed more active anticancer potential than other triterpenoid saponins. In this study, we determined the in vivo effects of PPD in a mouse cancer model first. Then, using human colorectal cancer cell lines, we observed significant cancer cell growth inhibition by promoting G1 cell cycle redistribution and apoptosis. Subsequently, we characterized the downstream genes targeted by PPD in HCT-116 cancer cells. Using Affymetrix high density GeneChips, we obtained the gene expression profile of the cells. Microarray data indicated that the expression levels of 76 genes were changed over two-fold after PPD, of which 52 were upregulated while the remaining 24 were downregulated. Ingenuity pathway analysis of top functions affected was carried out. Data suggested that by regulating the interactions between p53 and DR4/DR5, the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway played a key role in the action of PPD, a promising colon cancer inhibitory compound.

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“…PPD, PPD11 and PPD12 were synthesized by our lab as previously reported [ 25 ] and prepared as a 100 mM stock solution in DMSO for in vitro studies. Verapamil (VRP), Adriamycin (ADM), Rhodamine 123 (Rho123), cisplatin (CDDP) and other chemicals were purchased from Sigma Chemical Co (St. Louis, MO, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Given the extremely low toxicity of the compound, PPD is an attractive candidate as a chemo-sensitizer for treatment of MDR tumors [ 21 – 24 ]. To improve the effects of PPD, we previously designed and synthesized a series of PPD derivatives with aromatic substituted aliphatic amine at the 24 positions [ 25 ]. In this study, we demonstrate that PPD12, compared to its parental compound PPD and inactive compound PPD11, sensitizes ABCB1-medidated MDR cancer cells to chemotherapeutic agents in vitro and in vivo .…”

Section: Introductionmentioning

confidence: 99%

A 20(S)-protopanoxadiol derivative overcomes multi-drug resistance by antagonizing ATP-binding cassette subfamily B member 1 transporter function

et al. 2016

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In cancer cells, failure of chemotherapy is often caused by the ATP-binding cassette subfamily B member 1 (ABCB1), and few drugs have been successfully developed to overcome ABCB1-mediated multi-drug resistance (MDR). To suppress ABCB1 activity, we previously designed and synthesized a new series of derivatives based on 20(S)-protopanoxadiol (PPD). In the present study, we investigated the role of PPD derivatives in the function of ABC transporters. Non-toxic concentrations of the PPD derivative PPD12 sensitized ABCB1-overexpressing cells to their anti-cancer substrates better than either the parental PPD or inactive PPD11. PPD12 increased intracellular accumulation of adriamycin and rhodamine123 in resistant cancer cells. Although PPD12 did not suppress the expression of ABCB1 mRNA or protein, it stimulated the activity of ABCB1 ATPase. Because PPD12 is a competitive inhibitor, it was predicted to bind to the large hydrophobic cavity of homology-modeled human ABCB1. PPD12 also enhanced the efficacy of adriamycin against ABCB1-overexpressing KB/VCR xenografts in nude mice. In conclusion, PPD12 enhances the efficacy of substrate drugs in ABCB1-overexpressing cancer cells. These findings suggest that a combination therapy consisting of PPD12 with conventional chemotherapeutic agents may be an effective treatment for ABCB1-mediated MDR cancer patients.

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20(S)-Protopanaxadiol (PPD) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs

Cited by 19 publications

References 27 publications

Semi-synthetic ocotillol analogues as selective ABCB1-mediated drug resistance reversal agents

Semi-synthetic ocotillol analogues as selective ABCB1-mediated drug resistance reversal agents

TRAIL pathway is associated with inhibition of colon cancer by protopanaxadiol

A 20(S)-protopanoxadiol derivative overcomes multi-drug resistance by antagonizing ATP-binding cassette subfamily B member 1 transporter function

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