Combined treatment with TRAIL and PPARγ ligands overcomes chemoresistance of ovarian cancer cell lines

Bräutigam, Karen; Biernath-Wüpping, Julia; Bauerschlag, Dirk; Kaisenberg, Constantin S. von; Jonat, W.; Maass, Nicolaì; Arnold, Norbert; Meinhold‐Heerlein, Ivo

doi:10.1007/s00432-010-0952-2

Cited by 28 publications

(24 citation statements)

References 54 publications

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“…Studies have shown the antineoplastic effects of PPARγ ligands in various preclinical models (51); however, agonists of these receptors used as monotherapy failed to exert therapeutic benefits in advanced stage breast patients (52). Notably, PPARγ agonists in combination with the conventional antineoplastic drugs, such as carboplatin or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), showed synergistic effects, indicating that differentiation induced by PPARγ activation restored sensitivity to the cytotoxic drug (53,54). These synergistic effects were replicated in cells treated with DOX + I 2 in both preclinical (16) and clinical studies (17), supporting the notion that some I 2 effects are mediated by PPARγ activation.…”

Section: Discussionmentioning

confidence: 99%

Molecular iodine impairs chemoresistance mechanisms, enhances doxorubicin retention and induces downregulation of the CD44+/CD24+ and E-cadherin+/vimentin+ subpopulations in MCF-7 cells resistant to low doses of doxorubicin

et al. 2017

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One of the most dreaded clinical events for an oncology patient is resistance to treatment. Chemoresistance is a complex phenomenon based on alterations in apoptosis, the cell cycle and drug metabolism, and it correlates with the cancer stem cell phenotype and/or epithelial-mesenchymal transition. Molecular iodine (I2) exerts an antitumor effect on different types of iodine-capturing neoplasms by its oxidant/antioxidant properties and formation of iodolipids. In the present study, wild-type breast carcinoma cells (MCF-7/W) were treated chronically with 10 nM doxorubicin (DOX) to establish a low-dose DOX-resistant mammary cancer model (MCF-7/D). MCF-7/D cells were established after 30 days of treatment when the culture showed a proliferation rate similar to that of MCF-7/W. These DOX-resistant cells also showed increases in p21, Bcl-2 and MDR-1 expression. Supplementation with 200 µM I2 exerted similar effects in both cell lines: it decreased the proliferation rate by ~40%, and I2 co-administration with DOX significantly increased the inhibitory effect (to ~60%) and also increased apoptosis (BAX/Bcl-2 index), principally by inhibiting Bcl-2 expression. The inhibition by I2 + DOX was also accompanied by impaired MDR-1 induction as well as by a significant increase in PPARγ expression. All of these changes could be attributed to enhanced DOX retention and differential down-selection of CD44+/CD24+ and E-cadherin+/vimentin+ subpopulations. I2 + DOX-selected cells showed a weak induction of xenografts in Foxn1nu/nu mice, indicating that the iodine supplements reversed the tumorogenic capacity of the MCF-7/D cells. In conclusion, I2 is able to reduce the drug resistance and invasive capacity of mammary cancer cells exposed to DOX and represents an anti-chemoresistance agent with clinical potential.

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Section: Discussionmentioning

confidence: 99%

Molecular iodine impairs chemoresistance mechanisms, enhances doxorubicin retention and induces downregulation of the CD44+/CD24+ and E-cadherin+/vimentin+ subpopulations in MCF-7 cells resistant to low doses of doxorubicin

et al. 2017

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“…For example, weight gain or bone fractures observed in response to administration of PPARγ agonists 187–190, 206 might be offset by agonist activity for PPARα or PPARβ/δ, which can increase lipid catabolism and stimulate osteoblast activity in bone 208 . As there is also good evidence that combining PPAR activation with other chemopreventive or chemotherapeutic agents can significantly increase anti-cancer activities 92, 209–220 , it remains possible that dual or pan PPAR agonists could lead to even greater improvement in efficacy.…”

Section: Ppars and Cancer Treatment And Preventionmentioning

confidence: 99%

The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention

2012

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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in regulating glucose and lipid homeostasis, inflammation, proliferation and differentiation. Although all of these functions might contribute to the influence of PPARs in carcinogenesis, there is a distinct need for a balanced review of the literature and additional experimentation to determine the potential for targeting PPARs for cancer therapy and cancer chemoprevention. As PPAR agonists include drugs used for the treatment of metabolic diseases, a more complete understanding of the roles of PPARs in cancer will aid in determining any increased cancer risk for patients undergoing therapy with PPAR agonists.

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“…TRO treatment showed no effect on proliferation on its own; however, when combined with TRAIL, that reduced cell numbers in etoposide-, pemetrexed-, cisplatin-, docetaxel-, and gemcitabine-resistant cell lines. Similarly, 15d-PGJ 2 treatment inhibited growth in all cell lines, especially the HEY cell line which was developed by the authors [43]. …”

Section: Cell Signaling Moleculesmentioning

confidence: 99%

The Key to Unlocking the Chemotherapeutic Potential of PPARγLigands: Having the Right Combination

Skelhorne‐Gross

Nicol

2012

PPAR Research

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Despite extensive preclinical evidence that peroxisome proliferator-activated receptor (PPAR)γ activation protects against tumourigenesis, results from a few clinical trials using PPARγ ligands as monotherapy show modest success. In spite of this, several groups reported exciting results with therapeutic regimens that combine PPARγ ligands with other compounds: chemotherapeutic agents, retinoid x receptor (RXR)α agonists, statins, or cell-to-cell signaling molecules in preclinical cancer models and human trials. Here we have compiled an extensive review, consolidating the existing literature, which overwhelmingly supports a beneficial effect of treating with PPARγ ligands in combination with existing chemotherapies versus their monotherapy in cancer. There are many examples in which combination therapy resulted in synergistic/additive effects on apoptosis, differentiation, and the ability to reduce cell growth and tumour burden. There are also studies that indicate that PPARγ ligand pretreatment overcomes resistance and reduces toxicities. Several mechanisms are explored to explain these protective effects. This paper highlights each of these studies that, collectively, make a very strong case for the use of PPARγ ligands in combination with other agents in the treatment and management of several cancers.

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Combined treatment with TRAIL and PPARγ ligands overcomes chemoresistance of ovarian cancer cell lines

Abstract: Therefore, the combinational treatment with TRAIL and PPARγ ligands might be a promising experimental therapy because the PPARγ ligands, especially d15-PGJ(2), sensitize drug-resistant ovarian cancer cells to TRAIL-induced apoptosis.

Cited by 28 publications

References 54 publications

Molecular iodine impairs chemoresistance mechanisms, enhances doxorubicin retention and induces downregulation of the CD44+/CD24+ and E-cadherin+/vimentin+ subpopulations in MCF-7 cells resistant to low doses of doxorubicin

Molecular iodine impairs chemoresistance mechanisms, enhances doxorubicin retention and induces downregulation of the CD44+/CD24+ and E-cadherin+/vimentin+ subpopulations in MCF-7 cells resistant to low doses of doxorubicin

The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention

The Key to Unlocking the Chemotherapeutic Potential of PPARγLigands: Having the Right Combination

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