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  1. Article: In vitro anticancer efficacy of a polyphenolic combination of Quercetin, Curcumin, and Berberine in triple negative breast cancer (TNBC) cells

    Kashyap, Akanksha / Umar, Sheikh Mohammad / Dev J․R․, Arundhathi / Mendiratta, Mohini / Prasad, Chandra Prakash

    Phytomedicine plus. 2022 May, v. 2, no. 2

    2022  

    Abstract: Among all breast cancers, Triple negative breast cancer (TNBC) is the most aggressive subtype with an increased metastatic and relapse rate. Presently, the only therapeutic option available for TNBC patients is standard chemotherapy. Past research on ... ...

    Abstract Among all breast cancers, Triple negative breast cancer (TNBC) is the most aggressive subtype with an increased metastatic and relapse rate. Presently, the only therapeutic option available for TNBC patients is standard chemotherapy. Past research on natural compounds has demonstrated their chemopreventive as well as therapeutic effects in various cancers. Compounds like quercetin (QUE), curcumin (CUR), and berberine (BBR) have been shown to induce pro-apoptotic, anti-proliferative, anti-migratory, and anti-metastatic effects in various cancers. In the present study, we investigated the therapeutic potential of three natural compounds (QUE, CUR, and BBR) in the in vitro TNBC models. We also hypothesized that compared to their individual effects, combination treatment of all three polyphenols might enhance their in vitro efficacy in TNBCs. Using MDA-MB-468 and MDA-MB-231 as TNBC cell line models, we evaluated the effect of individual phytochemicals as well as their combined treatment (COMQᵁᴱ⁺Cᵁᴿ⁺ᴮᴮᴿ) on Epithelial mesenchymal transition (EMT) statuses, migration potential, cancer stem cells (CSCs), clonogenic/3D matrigel growth capability and drug resistance in TNBC cells. Our data demonstrated that the effect induced by the combination (COMQᵁᴱ⁺Cᵁᴿ⁺ᴮᴮᴿ) treatment on EMT proteins and cell migration were significant and synergistic, compared with individual treatments. Additionally, COMQᵁᴱ⁺Cᵁᴿ⁺ᴮᴮᴿ treatment significantly impaired the CD44⁺/CD24⁻population, clonogenic potential, and inherent cisplatin resistance in TNBC cells. For all our combination experiments, we have used 1/10thdose (to their respective IC₅₀concentrations), thereby showing strong efficacy of these phytochemicals in TNBC models. These findings demonstrate for the first time that combination QUE, CUR, and BBR has potential in the treatment of TNBCs, owing to its anti-proliferative, EMT inhibitory, and antagonistic cancer stemness functions.
    Keywords apoptosis ; berberine ; breast neoplasms ; breasts ; cell lines ; cell movement ; chemoprevention ; cisplatin ; curcumin ; drug resistance ; drug therapy ; epithelium ; metastasis ; polyphenols ; quercetin ; relapse
    Language English
    Dates of publication 2022-05
    Publishing place Elsevier B.V.
    Document type Article
    ISSN 2667-0313
    DOI 10.1016/j.phyplu.2022.100265
    Database NAL-Catalogue (AGRICOLA)

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  2. Article: Quercetin Impairs HuR-Driven Progression and Migration of Triple Negative Breast Cancer (TNBC) Cells

    Umar, Sheikh Mohammad / Patra, Sushmita / Kashyap, Akanksha / Dev J R, Arundhathi / Kumar, Lalit / Prasad, Chandra Prakash

    Nutrition and cancer. 2022 Apr. 21, v. 74, no. 4

    2022  

    Abstract: In the present study, we have explored the prognostic value of HuR gene as well as protein in breast cancers. Furthermore, we have also investigated the HuR therapeutic relevance in TNBCs, which is an aggressive breast cancer subtype. Using an online ... ...

    Abstract In the present study, we have explored the prognostic value of HuR gene as well as protein in breast cancers. Furthermore, we have also investigated the HuR therapeutic relevance in TNBCs, which is an aggressive breast cancer subtype. Using an online meta-analysis tool, we found that HuR protein overexpression positively correlates with reduced overall survival of TNBC patients (p = 0.028). Furthermore, we demonstrated that the TNBC breast cancer cell lines i.e., MDA-MB-231 and MDA-MB-468 are good model systems to study HuR protein, as they both exhibit a significant amount of cytoplasmic HuR (active form). Quercetin treatment significantly inhibited the cytoplasmic HuR in both TNBC cell lines. By using specific HuR siRNA, we established that quercetin-mediated inhibition of adhesion and migration of TNBC cells is dependent on HuR. Upon analyzing adhesion proteins i.e., β-catenin and CD44, we found that quercetin mediated effect on TNBC adhesion and migration was through the HuR-β-catenin axis and CD44, independently. Overall, the present results demonstrate that elevated HuR levels are associated with TNBC progression and relapse, and the ability of quercetin to inhibit cytoplasmic HuR protein provides a rationale for using it as an anticancer agent for the treatment of aggressive TNBCs. Supplemental data for this article is available online at at 10.1080/01635581.2021.1952628.
    Keywords adhesion ; antineoplastic agents ; breast neoplasms ; breasts ; genes ; meta-analysis ; neoplasm cells ; quercetin ; relapse ; therapeutics
    Language English
    Dates of publication 2022-0421
    Size p. 1497-1510.
    Publishing place Taylor & Francis
    Document type Article
    ZDB-ID 424433-3
    ISSN 1532-7914 ; 0163-5581
    ISSN (online) 1532-7914
    ISSN 0163-5581
    DOI 10.1080/01635581.2021.1952628
    Database NAL-Catalogue (AGRICOLA)

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  3. Article ; Online: Dihydrotanshinone-I modulates Epithelial Mesenchymal Transition (EMT) Thereby Impairing Migration and Clonogenicity of Triple Negative Breast Cancer Cells.

    Kashyap, Akanksha / Umar, Sheikh Mohammad / Dev J R, Arundhathi / Prasad, Chandra Prakash

    Asian Pacific journal of cancer prevention : APJCP

    2021  Volume 22, Issue 7, Page(s) 2177–2184

    Abstract: Background: Salvia miltiorrhiza Bunge (Danshen), has been used for its therapeutic value in Traditional Chinese Medicine (TCM), for almost a thousand years. Dihydrotanshinone-I (DHTS) is a lipophilic compound isolated from the plant Salvia miltiorrhiza ... ...

    Abstract Background: Salvia miltiorrhiza Bunge (Danshen), has been used for its therapeutic value in Traditional Chinese Medicine (TCM), for almost a thousand years. Dihydrotanshinone-I (DHTS) is a lipophilic compound isolated from the plant Salvia miltiorrhiza that has been shown to induce anti-proliferative and apoptotic effects on breast cancer cells. In the present study, we investigated the anti-migratory effect of DHTS on TNBC cell lines by studying the Epithelial Mesenchymal Transition (EMT) changes.
    Methods: IC50 values for DHTS in TNBC breast cancer cells were either discovered by literature search or by performing MTT assay. DHTS effect on EMT markers (viz. CD44, E-cadherin, Vimentin, N-cadherin, and active β-catenin) was studied using western blotting. Association between EMT and migration was further carried out in DHTS treated TNBC cells by wound healing assay. Cancer stemness and proliferation potential were further accessed using colony formation assay.
    Results: MTT assay revealed IC50 of MDA-MB-468 cells at 2 µM for 24 h. Subsequently, DHTS treatment in TNBC cell lines (MDA-MB-468 and MDA-MB-231) led to decrease in mesenchymal markers i.e. vimentin, N-cadherin and, active β-catenin. DHTS treated MDA-MB-468 cells showed a decrease in adhesion protein CD44 and an increase in epithelial protein E-cadherin. Additionally, a decrease in EMT potential was positively associated with the inhibition of migration and clonogenic potential in DHTS treated TNBC cells.
    Conclusion: In this study, we have demonstrated for the first time that DHTS has the potential to inhibit the migration and clonogenicity of highly aggressive TNBC cells by obstructing Epithelial to Mesenchymal Transition.
    MeSH term(s) Biomarkers, Tumor/metabolism ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Epithelial-Mesenchymal Transition/drug effects ; Furans/pharmacology ; Humans ; Phenanthrenes/pharmacology ; Plant Extracts/pharmacology ; Quinones/pharmacology ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/metabolism
    Chemical Substances Biomarkers, Tumor ; Furans ; Phenanthrenes ; Plant Extracts ; Quinones ; dihydrotanshinone I (562G9360V6)
    Language English
    Publishing date 2021-07-01
    Publishing country Thailand
    Document type Journal Article
    ZDB-ID 2218955-5
    ISSN 2476-762X ; 1513-7368
    ISSN (online) 2476-762X
    ISSN 1513-7368
    DOI 10.31557/APJCP.2021.22.7.2177
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Combination of 3PO analog PFK15 and siPFKL efficiently suppresses the migration, colony formation ability, and PFK-1 activity of triple-negative breast cancers by reducing the glycolysis.

    Kashyap, Akanksha / Umar, Sheikh Mohammad / Dev J R, Arundhathi / Mathur, Sandeep R / Gogia, Ajay / Batra, Atul / Deo, S V S / Prasad, Chandra Prakash

    Journal of cellular biochemistry

    2023  Volume 124, Issue 9, Page(s) 1259–1272

    Abstract: Among all the subtypes of breast cancer, triple-negative breast cancer (TNBC) has been associated with the worst prognosis. Recently, for many solid tumors (including breast cancer) metabolic reprogramming has appeared as a cancer cell hallmark, and the ... ...

    Abstract Among all the subtypes of breast cancer, triple-negative breast cancer (TNBC) has been associated with the worst prognosis. Recently, for many solid tumors (including breast cancer) metabolic reprogramming has appeared as a cancer cell hallmark, and the elevated glycolytic pathway has been linked to their aggressive phenotype. In the present study, we evaluated the prognostic and therapeutic relevance of PFKFB3 (6-phosphofructo-2- kinase/fructose-2,6-bisphosphatase) in TNBCs. Prognostic significance of PFKFB3 expression was evaluated in overall breast cancers as well as in TNBCs. PFKFB3 inhibitor (3PO potent analogue i.e., PFK15) cytotoxicity in TNBC cell lines (MDA-MB-231 and MDA-MB-468) was analyzed using an MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Cancer cell physiological characteristics like clonogenicity and migration were also investigated after PFK15 treatment. As fructose-2,6-bisphosphate (F-2,6-BP), has been associated with increased PFK-1 activity, the effect of PFKFB3 inhibition by PFK15 was investigated on two major isoforms of phosphofructokinase-1 (PFK-1) in breast cancer, that is, phosphofructokinase-platelet type (PFKP) and phosphofructokinase-liver type (PFKL) (relevant to breast cancer). For PFKL inhibition, the siRNA approach was used. PFKFB3 expression was significantly correlated with inferior overall survival in breast cancer patients including TNBCs. PFK15 treatment in TNBC cells (i.e., MDA-MB-231 and MDA-MB-468) resulted in a decreased PFKP expression, thereby leading to reduced colony formation ability, migration rate, and extracellular lactate levels. However, to our surprise PFK15 treatment in both TNBC cells also resulted in elevated PFKL levels. Our results demonstrated that the combinatorial inhibition of PFK15 with siPFKL was more effective in TNBC cells, as it led to a decrease in colony formation ability, migration rate, extracellular lactate levels, and PFK-1 activity when compared with individual treatments. Using bona fide PFKFB3 inhibitor, that is, AZ67, we further show that AZ67 treatment to TNBC cells has no effect either on the expression of PFKP and PFKL, or on the lactate production. In summary, our present in vitro study demonstrated that 3PO derived PFK15 mechanism of action is totally different from AZ67 in TNBC cells. However, we advocate that the PFK15-mediated inhibition (along with PFKL) on the TNBCs migration, colony formation, and PFK-1 activity can be further explored for the therapeutic advantage of TNBC patients.
    MeSH term(s) Humans ; Triple Negative Breast Neoplasms/drug therapy ; Cell Proliferation ; Glycolysis ; Phosphofructokinase-2/genetics ; Phosphofructokinase-2/metabolism ; Lactates/pharmacology ; Cell Line, Tumor
    Chemical Substances PFK15 ; Phosphofructokinase-2 (EC 2.7.1.105) ; Lactates
    Language English
    Publishing date 2023-07-14
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 392402-6
    ISSN 1097-4644 ; 0730-2312
    ISSN (online) 1097-4644
    ISSN 0730-2312
    DOI 10.1002/jcb.30443
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Quercetin Impairs HuR-Driven Progression and Migration of Triple Negative Breast Cancer (TNBC) Cells.

    Umar, Sheikh Mohammad / Patra, Sushmita / Kashyap, Akanksha / Dev J R, Arundhathi / Kumar, Lalit / Prasad, Chandra Prakash

    Nutrition and cancer

    2021  Volume 74, Issue 4, Page(s) 1497–1510

    Abstract: In the present study, we have explored the prognostic value of HuR gene as well as protein in breast cancers. Furthermore, we have also investigated the HuR therapeutic relevance in TNBCs, which is an aggressive breast cancer subtype. Using an online ... ...

    Abstract In the present study, we have explored the prognostic value of HuR gene as well as protein in breast cancers. Furthermore, we have also investigated the HuR therapeutic relevance in TNBCs, which is an aggressive breast cancer subtype. Using an online meta-analysis tool, we found that HuR protein overexpression positively correlates with reduced overall survival of TNBC patients (
    MeSH term(s) Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; ELAV-Like Protein 1/genetics ; Humans ; Quercetin/pharmacology ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/metabolism ; beta Catenin/genetics ; beta Catenin/metabolism
    Chemical Substances ELAV-Like Protein 1 ; beta Catenin ; Quercetin (9IKM0I5T1E)
    Language English
    Publishing date 2021-07-19
    Publishing country United States
    Document type Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't
    ZDB-ID 424433-3
    ISSN 1532-7914 ; 0163-5581
    ISSN (online) 1532-7914
    ISSN 0163-5581
    DOI 10.1080/01635581.2021.1952628
    Database MEDical Literature Analysis and Retrieval System OnLINE

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