Elimination of ALDH+ breast tumor initiating cells by docosahexanoic acid and/or gamma tocotrienol through SHP-1 inhibition of Stat3 signaling

Xiong, Ailian; Yu, Weiping; Liu, Yaobin; Sanders, Bob G.; Kline, Kimberly

doi:10.1002/mc.22291

Cited by 24 publications

(18 citation statements)

References 53 publications

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“…STAT3 inhibition in cancer cells appeared to be involved in the apoptotic process promoted by DHA, as STAT3 de-phosphorylation was associated with cancer cell death and treatment with a phosphatase inhibitor inhibited the cancer cell death. Our findings are consistent with previous data, showing the capability of DHA to inhibit STAT3 in other tumor cell models [54, 55]. Moreover, new data have shown that STAT3 inhibitors, in combinatorial therapy with anthracycline-based immunogenic chemotherapy, potentiated the immunogenic chemotherapy [32].…”

Section: Discussionsupporting

confidence: 93%

Docosahexaenoic acid (DHA) promotes immunogenic apoptosis in human multiple myeloma cells, induces autophagy and inhibits STAT3 in both tumor and dendritic cells

et al. 2017

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Docosahexaenoic acid (DHA), a ω-3 polyunsaturated fatty acid found in fish oil, is a multi-target agent and exerts anti-inflammatory and anticancer activities alone or in combination with chemotherapies. Combinatorial anticancer therapies, which induce immunogenic apoptosis, autophagy and STAT3 inhibition have been proposed for long-term therapeutic success. Here, we found that DHA promoted immunogenic apoptosis in multiple myeloma (MM) cells, with no toxicity on PBMCs and DCs. Immunogenic apoptosis was shown by the emission of specific DAMPs (CRT, HSP90, HMGB1) by apoptotic MM cells and the activation of their pro-apoptotic autophagy. Moreover, immunogenic apoptosis was directly shown by the activation of DCs by DHA-induced apoptotic MM cells. Furthermore, we provided the first evidence that DHA activated autophagy in PBMCs and DCs, thus potentially acting as immune stimulator and enhancing processing and presentation of tumor antigens by DCs. Finally, we found that DHA inhibited STAT3 in MM cells. STAT3 pathway, essential for MM survival, contributed to cancer cell apoptosis by DHA. We also found that DHA inhibited STAT3 in blood immune cells and counteracted STAT3 activation by tumor cell-released factors in PBMCs and DCs, suggesting the potential enhancement of the anti-tumor function of multiple immune cells and, in particular, that of DCs.

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Section: Discussionsupporting

confidence: 93%

Docosahexaenoic acid (DHA) promotes immunogenic apoptosis in human multiple myeloma cells, induces autophagy and inhibits STAT3 in both tumor and dendritic cells

et al. 2017

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“…Pece et al, [41] have shown that PKH26 dye retention can be used to visualize and distinguish tumor stem cells in situ among the population of more actively proliferating cells. Note that although SUM159 is triple negative, highly undifferentiated, and stem-like in nature, it is still hierarchically organized, and only a small proportion of the cells within the population are actually stem cells [42, 43]. …”

Section: Resultsmentioning

confidence: 99%

IRES inhibition induces terminal differentiation and synchronized death in triple-negative breast cancer and glioblastoma cells

et al. 2016

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Internal ribosome entry site (IRES)-mediated translation is a specialized mode of protein synthesis which malignant cells depend on to survive adverse microenvironmental conditions. Our lab recently reported the identification of a group of compounds which selectively interfere with IRES-mediated translation, completely blocking de novo IGF1R synthesis, and differentially modulating synthesis of the two c-Myc isoforms. Here, we examine the phenotypic consequences of sustained IRES inhibition in human triple-negative breast carcinoma and glioblastoma cells. A sudden loss of viability affects the entire tumor cell population after ∼72-h continuous exposure to the lead compound. The extraordinarily steep dose-response relationship (Hill-Slope coefficients −15 to −35) and extensive physical connections established between the cells indicate that the cells respond to IRES inhibition collectively as a population rather than as individual cells. Prior to death, the treated cells exhibit prominent features of terminal differentiation, with marked gains in cytoskeletal organization, planar polarity, and formation of tight junctions or neuronal processes. In addition to IGF1R and Myc, specific changes in connexin 43, BiP, CHOP, p21, and p27 also correlate with phenotypic outcome. This unusual mode of tumor cell death is absolutely dependent on exceeding a critical threshold in cell density, suggesting that a quorum-sensing mechanism may be operative. Death of putative tumor stem cells visualized in situ helps to explain the inability of tumor cells to recover and repopulate once the compound is removed. Together, these findings support the concept that IRES-mediated translation is of fundamental importance to maintenance of the undifferentiated phenotype and survival of undifferentiated malignant cells.Electronic supplementary materialThe online version of this article (doi:10.1007/s13277-016-5161-4) contains supplementary material, which is available to authorized users.

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“…In fact, DSF-induced suppression of CSCs has been extensively studied and well-recognized [23]. Meanwhile, in vitro and/or in vivo studies have confirmed that DHA also possesses the potential to eliminate CSCs [55–58]. Therefore, mammosphere formation and ELDA assay were applied to test whether DSF's inhibitory action on CSCs is enhanced by DHA.…”

Section: Discussionmentioning

confidence: 99%

Docosahexaenoic acid and disulfiram act in concert to kill cancer cells: a mutual enhancement of their anticancer actions

et al. 2017

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We previously reported a synergistic anticancer action of clioquinol and docosahexaenoic acid (DHA) in human cancer cells. However, clioquinol has been banned from the clinic due to its neurotoxicity. This study identified disulfiram (DSF) as a substitute compound to clioquinol, acting in concert with DHA to more effectively kill cancer cells and suppress tumor growth. Treatment with DSF and DHA induced greater apoptotic cell death and suppression of tumor growth in vitro and in vivo, as compared to DSF and DHA used alone. Mechanistic studies demonstrated that DSF enhances DHA-induced cellular oxidative stress as evidenced by up-regulation of Nrf2-mediated heme oxygenase 1 (HO-1) gene transcription. On the other hand, DHA was found to enhance DSF-induced suppression of mammosphere formation and stem cell frequency in a selected cancer model system, indicating that alterations to cancer cell stemness are involved in the combinatory anticancer action of DSF and DHA. Thus, DHA and DSF, both clinically approved drugs, act in concert to more effectively kill cancer cells. This combinatory action involves an enhancement of cellular oxidative stress and suppression of cancer cell stemness.

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Elimination of ALDH+ breast tumor initiating cells by docosahexanoic acid and/or gamma tocotrienol through SHP-1 inhibition of Stat3 signaling

Cited by 24 publications

References 53 publications

Docosahexaenoic acid (DHA) promotes immunogenic apoptosis in human multiple myeloma cells, induces autophagy and inhibits STAT3 in both tumor and dendritic cells

Docosahexaenoic acid (DHA) promotes immunogenic apoptosis in human multiple myeloma cells, induces autophagy and inhibits STAT3 in both tumor and dendritic cells

IRES inhibition induces terminal differentiation and synchronized death in triple-negative breast cancer and glioblastoma cells

Docosahexaenoic acid and disulfiram act in concert to kill cancer cells: a mutual enhancement of their anticancer actions

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