Inhibition of hyaluronic acid formation sensitizes chronic myelogenous leukemia to treatment with doxorubicin

Uchakina, Olga N.; Ban, Hao; Hostetler, Bryan; McKallip, Robert J.

doi:10.1093/glycob/cww064

Cited by 9 publications

(6 citation statements)

References 41 publications

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“…HAS2 and HAS3 were similarly increased in OV-90 CBP cells that acquired CBP resistance compared to parental OV-90 cells. Recent studies have also shown that leukemic cell lines with increased HA production resist chemotherapy [23,24]. Together, these findings support the concept that HA plays an important role in the development of acquired chemotherapy resistance.…”

Section: Discussionsupporting

confidence: 66%

4-Methylumbelliferone Inhibits Cancer Stem Cell Activation and Overcomes Chemoresistance in Ovarian Cancer

Lokman

Price

Hawkins

et al. 2019

Cancers

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We have recently shown that the extracellular matrix molecule hyaluronan (HA) plays a role in the development of ovarian cancer chemoresistance. This present study determined if HA production is increased in chemotherapy-resistant ovarian cancers and if the HA inhibitor 4-methylubelliferone (4-MU) can overcome chemoresistance to the chemotherapeutic drug carboplatin (CBP) and inhibit spheroid formation and the expression of cancer stem cell (CSC) markers. We additionally assessed whether 4-MU could inhibit in vivo invasion of chemoresistant primary ovarian cancer cells in the chicken embryo chorioallantoic membrane (CAM) assay. The expression of the HA synthases HAS2 and HAS3 was significantly increased in chemoresistant compared to chemosensitive primary ovarian cancer cells isolated from patient ascites. 4-MU significantly inhibited HA production, cell survival, and spheroid formation of chemoresistant serous ovarian cancer cells. In combination with CBP, 4-MU treatment significantly decreased ovarian cancer cell survival and increased apoptosis of chemoresistant primary cells compared to CBP alone. 4-MU significantly reduced spheroid formation, expression of CSC markers ALDH1A1 and ABCG2 in primary cell spheroid cultures, and ALDH1 immunostaining in patient-derived tissue explant assays following treatment with CBP. Furthermore, 4-MU was very effective at inhibiting in vivo invasion of chemoresistant primary cells in CAM assays. Inhibition of HA is therefore a promising new strategy to overcome chemoresistance and to improve ovarian cancer survival.

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Section: Discussionsupporting

confidence: 66%

4-Methylumbelliferone Inhibits Cancer Stem Cell Activation and Overcomes Chemoresistance in Ovarian Cancer

Lokman

Price

Hawkins

et al. 2019

Cancers

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“…The antitumor effect results from reduced CD44 activation that lowers PI3K signaling and AKT and ERK phosphorylation (Kundu et al, 2013;Lompardia et al, 2017). Others have shown that 4-MU increases p38 activation and caspase-3, caspase-9, and PARP cleavage, explaining not only the apoptotic effect but might also indicate an increased sensitivity toward cytotoxic stress (Lokeshwar et al, 2010;Uchakina et al, 2016). Importantly, these proapoptotic effects can be rescued by HA addition to cultured cells, demonstrating that these are direct results of reduction in HAS activity and not off-target effects.…”

Section: Targeting Hyaluronan Synthesismentioning

confidence: 99%

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

Henke

Nandigama

Ergün

2020

Front. Mol. Biosci.

771

613

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Solid tumors are complex organ-like structures that consist not only of tumor cells but also of vasculature, extracellular matrix (ECM), stromal, and immune cells. Often, this tumor microenvironment (TME) comprises the larger part of the overall tumor mass. Like the other components of the TME, the ECM in solid tumors differs significantly from that in normal organs. Intratumoral signaling, transport mechanisms, metabolisms, oxygenation, and immunogenicity are strongly affected if not controlled by the ECM. Exerting this regulatory control, the ECM does not only influence malignancy and growth of the tumor but also its response toward therapy. Understanding the particularities of the ECM in solid tumor is necessary to develop approaches to interfere with its negative effect. In this review, we will also highlight the current understanding of the physical, cellular, and molecular mechanisms by which the pathological tumor ECM affects the efficiency of radio-, chemo-, and immunotherapy. Finally, we will discuss the various strategies to target and modify the tumor ECM and how they could be utilized to improve response to therapy.

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“…These authors also showed the proapoptotic effect of 4-MU in vivo, where treatment of tumorbearing mice with 4-MU significantly reduced tumor growth through the induction of apoptosis (62). These results, together with those of other studies, determine the role of 4-MU as a molecule that favors the response of CML to chemotherapy (63,64) and suggest that 4-MU is an excellent candidate for use in combination with conventional therapeutic strategies.…”

Section: Chronic Myeloid Leukemiasmentioning

confidence: 61%

“…Similarly, different studies have proposed 4-MU as a candidate molecule for co-adjuvant treatments for CML. Uchakina et al showed that 4-MU sensitizes K562 cells to doxorubicin treatment, by inhibiting HA synthesis and increasing apoptosis rates through p38 activation and PARP cleavage (63). Lompardıá et al found similar results when combining 4-MU treatment with the chemotherapeutic agent vincristine on K562 and K562 vincristine-resistant cells (Kv562) (64).…”

Section: -Mu Treatment As a New Strategy Of Co-adjuvant Drug On Conventional Antineoplastic Therapiesmentioning

confidence: 96%

Targeting the Tumor Extracellular Matrix by the Natural Molecule 4-Methylumbelliferone: A Complementary and Alternative Cancer Therapeutic Strategy

et al. 2021

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In antineoplastic therapy, one of the challenges is to adjust the treatment to the needs of each patient and reduce the toxicity caused by conventional antitumor strategies. It has been demonstrated that natural products with antitumoral properties are less toxic than chemotherapy and radiotherapy. Also, using already developed drugs allows developing substantially less costly methods for the discovery of new treatments than traditional drug development. Candidate molecules proposed for drug repositioning include 4-methylumbelliferone (4-MU), an orally available dietetic product, derivative of coumarin and mainly found in the plant family Umbelliferae or Apiaceae. 4-MU specifically inhibits the synthesis of glycosaminoglycan hyaluronan (HA), which is its main mechanism of action. This agent reduces the availability of HA substrates and inhibits the activity of different HA synthases. However, an effect independent of HA synthesis has also been observed. 4-MU acts as an inhibitor of tumor growth in different types of cancer. Particularly, 4-MU acts on the proliferation, migration and invasion abilities of tumor cells and inhibits the progression of cancer stem cells and the development of drug resistance. In addition, the effect of 4-MU impacts not only on tumor cells, but also on other components of the tumor microenvironment. Specifically, 4-MU can potentially act on immune, fibroblast and endothelial cells, and pro-tumor processes such as angiogenesis. Most of these effects are consistent with the altered functions of HA during tumor progression and can be interrupted by the action of 4-MU. While the potential advantage of 4-MU as an adjunct in cancer therapy could improve therapeutic efficacy and reduce toxicities of other antitumoral agents, the greatest challenge is the lack of scientific evidence to support its approval. Therefore, crucial human clinical studies have yet to be done to respond to this need. Here, we discuss and review the possible applications of 4-MU as an adjunct in conventional antineoplastic therapies, to achieve greater therapeutic success. We also describe the main proposed mechanisms of action that promote an increase in the efficacy of conventional antineoplastic strategies in different types of cancer and prospects that promote 4-MU repositioning and application in cancer therapy.

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Inhibition of hyaluronic acid formation sensitizes chronic myelogenous leukemia to treatment with doxorubicin

Cited by 9 publications

References 41 publications

4-Methylumbelliferone Inhibits Cancer Stem Cell Activation and Overcomes Chemoresistance in Ovarian Cancer

4-Methylumbelliferone Inhibits Cancer Stem Cell Activation and Overcomes Chemoresistance in Ovarian Cancer

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

Targeting the Tumor Extracellular Matrix by the Natural Molecule 4-Methylumbelliferone: A Complementary and Alternative Cancer Therapeutic Strategy

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