Novel diindolylmethane derivatives based NLC formulations to improve the oral bioavailability and anticancer effects in triple negative breast cancer

Godugu, Chandraiah; Doddapaneni, Ravi; Safe, Stephen; Singh, Mandip

doi:10.1016/j.ejpb.2016.08.006

Cited by 37 publications

(10 citation statements)

References 37 publications

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“…Important areas of bioactivity relevant to breast cancer chemoprevention include antioxidant effects, inhibition on COX-2 and other inflammatory response pathways [50]. Recent evidence of DIM derivatives as chemopreventive agents against triple negative breast cancer hold promise from early demonstration studies of in vitro models[51]. Tumor-specific responses have also been described including aryl hydrocarbon receptor (AhR) agonistic activity [52] and sensitizing activity against gamma radiation [53].…”

Section: Discussionmentioning

confidence: 99%

A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen

Thomson

Chow

Wertheim

et al. 2017

Breast Cancer Res Treat

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Purpose Diindolylmethane (DIM), a bioactive compound found in cruciferous vegetables, has proposed breast cancer chemoprevention activity. There is limited evidence of clinically relevant activity or long-term safety. A randomized, double-blind, placebo-controlled trial was conducted to determine the activity and safety of combined use of DIM (BR-DIM) with tamoxifen. Methods Women prescribed tamoxifen (n=130) were assigned to receive BioResponse-DIM® (BR-DIM), providing 150 mgs DIM twice daily, or placebo, for 12 months. The primary study endpoint was change in urinary 2/16 -hydroxyestrone (2/16 -OHE1) ratio. Change in 4-hydroxyestrone (4-OHE1), serum estrogens and sex hormone-binding globulin (SHBG), breast density, and tamoxifen metabolites also were assessed. Results Ninety-eight women (51 placebo, 47 DIM) completed intervention; compliance with treatment was >91%. DIM increased the 2/16 -OHE1 ratio (+3.2[0.8, 8.4]) compared to placebo (−0.7 [−1.7, 0.8], p <0.001). Serum SHBG also increased with DIM as compared to placebo (+ 25±22 and +1.1 ±19 nmol/L, respectively). No change in breast density measured by mammography or by MRI was observed. Plasma tamoxifen metabolites (endoxifen, 4-OH tamoxifen, and N-desmethyl-tamoxifen) were reduced in women receiving DIM versus placebo (P <0.001). Minimal adverse events were reported and overall did not differ by treatment arm. Conclusion In patients taking tamoxifen for breast cancer, daily DIM promoted favorable changes in estrogen metabolism and circulating levels of SHBG. Further research is warranted to determine whether decreases in tamoxifen metabolites, including endoxifen, with DIM would attenuate the clinical benefit of tamoxifen.

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Section: Discussionmentioning

confidence: 99%

A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen

Thomson

Chow

Wertheim

et al. 2017

Breast Cancer Res Treat

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“…Triple negative breast cancer (TNBC) has more aggressive disease progression with limited treatment options due to the lack of standard chemotherapy 34 – 36 . However, multidrug resistance (MDR) in cancer cells has remained as a significant obstacle in the achievement of efficient chemotherapy 37 , 38 .…”

Section: Discussionmentioning

confidence: 99%

Reversal of drug-resistance by noscapine chemo-sensitization in docetaxel resistant triple negative breast cancer

Doddapaneni

Patel

Chowdhury

et al. 2017

Sci Rep

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Multidrug resistance (MDR) is a major impediment to cancer treatment. Here, for the first time, we investigated the chemo-sensitizing effect of Noscapine (Nos) at low concentrations in conjunction with docetaxel (DTX) to overcome drug resistance of triple negative breast cancer (TNBC). In vitro experiments showed that Nos significantly inhibited proliferation of TNBC wild type (p < 0.01) and drug resistant (p < 0.05) TNBC cells. Nos followed by DTX treatment notably increased the cell viability (~1.3 fold) markedly (p < 0.05) in 3D models compared to conventional 2D systems. In vivo oral administration of Nos (100 mg/kg) followed by intravenous DTX (5 mg/kg) liposome treatment revealed regression of xenograft tumors in both wild type (p < 0.001) and drug-resistant (p < 0.05) xenografts. In wild type xenografts, combination of Nos plus DTX group showed 5.49 and 3.25 fold reduction in tumor volume compared to Nos and DTX alone groups, respectively. In drug-resistant xenografts, tumor volume was decreased 2.33 and 1.41 fold in xenografts treated with Nos plus DTX significantly (p < 0.05) compared to Nos and DTX alone respectively and downregulated the expression of anti-apoptotic factors and multidrug resistance proteins. Collectively, chemo-sensitizing effect of Nos followed by DTX regime provide a promising chemotherapeutic strategy and its significant role for the treatment of drug-resistant TNBC.

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“…After 48 h, cells were fixed and stained with crystal violet and the width of the gaps was measured and images were captured. In untreated control MDA-MB-231 cells due to their high migratory potential, move into scratched gaps and narrow down the gaps (gap closure) [26]. …”

Section: Methodsmentioning

confidence: 99%

Honokiol nanomicellar formulation produced increased oral bioavailability and anticancer effects in triple negative breast cancer (TNBC)

Godugu

Doddapaneni

Singh

2017

Colloids and Surfaces B: Biointerfaces

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Triple negative breast cancer (TNBC), owing to its aggressive behavior and toxicity associated with available chemotherapy; currently no suitable therapy is available. Honokiol (HNK) is a promising anticancer drug but has poor bioavailability. In the current study, we evaluated the anticancer effects of an oral Honokiol nanomicellar (NM) formulation (size range of 20–40 nm) in vitro against various TNBC cells lines. Cytotoxicity, clonogenic and wound healing assays demonstrated the promising anticancer effects. In vitro Caco-2 permeability studies suggested increased absorption of Honokiol. Compared to HNK-FD, nanomicellar formulations resulted in significant increase in the oral bioavailability. Cmax (4.06 and 3.60-fold) and AUC (6.26 and 5.83-fold) were significantly increased in comparison to oral 40 and 80 mg/kg free drug respectively. Further, anticancer effects of these formulations were studied in BALB/c nude mice transplanted with orthotopic MDA-MB-231 cell induced xenografts. After 4 weeks of daily administration of HNK-NM formulation, significant reduction in the tumor volumes and weights compared to free drug (p < 0.001) treated groups was observed. Surprisingly, in some of the animals (25%), the treatment resulted in complete eradication of tumors. Increased apoptosis and antiangiogenic effect was observed in HNK-NM groups compared to free drug and untreated control animals. This is the first report demonstrating that HNK-FD possesses anticancer effects against TNBC.

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Novel diindolylmethane derivatives based NLC formulations to improve the oral bioavailability and anticancer effects in triple negative breast cancer

Cited by 37 publications

References 37 publications

A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen

A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen

Reversal of drug-resistance by noscapine chemo-sensitization in docetaxel resistant triple negative breast cancer

Honokiol nanomicellar formulation produced increased oral bioavailability and anticancer effects in triple negative breast cancer (TNBC)

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