Novel Suppressive Effects of Ketotifen on Migration and Invasion of MDA-MB-231 and HT-1080 Cancer Cells

Kim, Hyun Ji; Park, Mi Kyung; Kim, Soo Youl; Lee, Chang Hoon

doi:10.4062/biomolther.2014.081

Cited by 16 publications

(11 citation statements)

References 38 publications

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“…At 10 mM of ketotifen, the exosome released by HeLa, MCF7 and BT549 cells decreased by 70%, 45% and 30%, respectively. Surprisingly, the effect of ketotifen on exosome increases the sensitivity of cancer cells to doxorubicin and also suppresses the progression of cancer cells 49,72 . As ketotifen was reported to block calcium influx into cells, and It is shown that exosome release was regulated by calcium-dependent mechanisms, and inhibitors of calcium entry into the cells reduce exosome release 73,74 .…”

Section: Other Inhibitorsmentioning

confidence: 99%

Advances in the discovery of exosome inhibitors in cancer

Zhang

Lü

Liu

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Exosomes are small membrane vesicles released by most eukaryotic cells. They are considered to play an essential role in cell-to-cell communication, and It is also found that they serve as functional mediators in many severe diseases, including progression of various types of cancers. Inhibition of exosome release may slow the progression of some cancers; thus, exosome has been an attractive target for cancer treatment. Over the years, considerable efforts have been made to discover novel, highly potent and excellently selective exosome inhibitors. Most of these inhibitors are derived from synthetic compounds, some of which are currently existed drugs and found to have the potential to inhibit exosome release. In this review, we briefly discussed the development of exosome inhibitors that are currently discovered and provided guidance for the future development of inhibitors.

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Section: Other Inhibitorsmentioning

confidence: 99%

Advances in the discovery of exosome inhibitors in cancer

Zhang

Lü

Liu

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…This effect is believed to be mediated by a block of calcium entry into the cells. 2,5,14 In the present study, we investigated whether ketotifen would alter exosome release from cancer cells and whether this activity may enhance the anti-tumor effects of doxorubicin in three different cancer model cell lines, namely HeLa (in vitro model for cervix carcinoma), MCF7 (in vitro model for breast cancer) and BT549 (in vitro model for breast cancer). The ultimate goal is to open the door for developing pharmacological agents targeting exosome release and their role in supporting the growth of cancer cells and their resistance to cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of exosome release by ketotifen enhances sensitivity of cancer cells to doxorubicin

Khan

Saleh

Alawadhi

et al. 2017

Cancer Biology & Therapy

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Exosomes released from cancer cells support metastasis and growth of recipient cells and increase their resistance to chemotherapy. Therapeutic targeting of exosomes is a promising area in cancer research. Our aim is to test the effect of the mast cell stabilizer ketotifen on exosomes release from cancer cells and how this can modify their response to doxorubicin. Exosomes release from three cancer cell lines (MCF7, HeLa and BT549) was assessed by scan electron microscope and exosomes quantification kit. Doxorubicin export within exosomes was monitored flurometrically and cellular sensitivity to doxorubicin ± ketotifen was measured by sulphorhodamine-B and colony formation assays. The three cell lines release different amounts of exosomes with the highest quantity released from BT549 followed by MCF7 and then HeLa. Ketotifen (10 µmol L) reduced exosomes release in all three cell lines with different efficiency (HeLa>MCF7>BT549). Doxorubicin export via exosomes was highest in BT549, lower in HeLa and lowest in MCF7 cells. Pretreatment with ketotifen sensitized the cells to doxorubicin (HeLa>MCF7>BT549) with a sensitization factor of 27, 8 and 1.25 respectively. Increased sensitivity of cells to doxorubicin by ketotifen was proportional to its effect on exosomes release. Our data is the first report of ketotifen modulating exosomes release from cancer cells and opens the avenue for exosomes-targeting cancer therapy. The differential effects of ketotifen on doxorubicin exosomal export in the cell lines studied, suggests an opportunity of pharmacological enhancement of doxorubicin anti-tumor activity in some but not all cancer types.

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“…Two other antihistamines, clemastine and desloratadine, induced T-cell lymphoma cell apoptosis that are involved in downregulating signal transducer and activator of transcription 3 (STAT3) and cellular myelocytomatosis (c-Myc) activities [ 10 ]. Moreover, ketotifen decreased the cell migration and invasion of breast cancer and fibrosarcoma cells, and the underlying mechanisms were associated with inhibition of cell division cycle 42 (Cdc42), Rho, Rac, and matrix metalloproteinase (MMP)-9 expressions [ 11 ]. Loratadin, a long-acting, non-sedating antihistamine drug enhanced the radiation sensitivity and then disrupted the cell cycle progression of human colon carcinoma cells [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

The Antihistamine Deptropine Induces Hepatoma Cell Death through Blocking Autophagosome-Lysosome Fusion

Liang

Chang

Sheu

et al. 2020

Cancers

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Some antihistamines have exhibited significant antitumor activity alone or in combination with other therapies in in vitro and clinical studies. However, the underlying mechanisms of how antihistamines inhibit hepatocellular carcinoma proliferation are still unknown. We first screened the antiproliferation activity of 12 benzocycloheptene structural-analogue drugs, and results showed that deptropine was the most potent inhibitor of both Hep3B and HepG2 human hepatoma cells. Deptropine significantly increased light chain 3B-II (LC3B-II) expression but did not induce sequestosome 1 (SQSTM1/p62) degradation in either cell line. Interestingly, other autophagy-related proteins, such as autophagy-related 7 (ATG7), vacuolar protein sorting 34 (VPS34), phosphorylated adenosine 5′-monophosphate-activated protein kinase (AMPK), and phosphorylated protein kinase B (PKB, also known as Akt), exhibited no significant change in either deptropine-treated cell line. Deptropine also inhibited the processing of cathepsin L from its precursor form to its mature form. Immunofluorescence microscopy showed an increase of autophagosomes in deptropine-treated cells, but deptropine blocked the fusion between autophagosomes and lysosomes. In a xenograft nude mice model, 2.5 mg/kg deptropine showed a great inhibitory effect on Hep3B tumor growth. These results suggest that deptropine can induce in vitro and in vivo hepatoma cell death, and the underlying mechanisms might be mediated through inhibiting autophagy by blocking autophagosome-lysosome fusion.

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Novel Suppressive Effects of Ketotifen on Migration and Invasion of MDA-MB-231 and HT-1080 Cancer Cells

Cited by 16 publications

References 38 publications

Advances in the discovery of exosome inhibitors in cancer

Advances in the discovery of exosome inhibitors in cancer

Inhibition of exosome release by ketotifen enhances sensitivity of cancer cells to doxorubicin

The Antihistamine Deptropine Induces Hepatoma Cell Death through Blocking Autophagosome-Lysosome Fusion

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