Methanol Extract of Aerial Parts of Pavetta indica L. Enhances the Cytotoxic Effect of Doxorubicin and Induces Radiation Sensitization in MDA-MB-231 Triple-Negative Breast Cancer Cells

Pavetta indica L. is used in traditional medicine for the treatment of various diseases including hemorrhoids, headache, urinary conditions, ulcerated nose, and dropsy. However, no study has evaluated the anticancer effect of P. indica L. In this study, we found that a methanol extract of the leaves and branches of P. indica L. (MEPI) caused cell-cycle arrest at the sub-G1 phase and induced apoptosis, as indicated by the activation of caspase-8, -3, -7, and c-PARP. Western blotting revealed that MEPI significantly reduced the levels of markers of the epithelial-mesenchymal transition, such as Vimentin, Snail, Slug, and matrix metallopeptidase 9. Notably, the expression of multidrug resistance-associated protein 1 in triple negative breast cancer (TNBC) was significantly decreased by MEPI. Moreover, the co-treatment with MEPI and doxorubicin resulted in a synergistic reduction in cell viability. MEPI also induced radiation sensitization of TNBC cells. Gas chromatography-mass spectrometry analysis revealed that 5,6-dehydrokawain (DK) is the major constituent of MEPI. Interestingly, DK exerted significant anti-invasive and anti-metastatic effects. Our results provide a strong rationale for investigating the molecular mechanisms of action of MEPI in TNBC.

[1]  Y. Kim,et al.  Integrated transcriptome and in vitro analysis revealed anti-proliferative effect of citral in human stomach cancer through apoptosis , 2019, Scientific Reports.

[2]  Sen Chen,et al.  Cucurbitacin B Induces the Lysosomal Degradation of EGFR and Suppresses the CIP2A/PP2A/Akt Signaling Axis in Gefitinib-Resistant Non-Small Cell Lung Cancer , 2019, Molecules.

[3]  Ping Zhang,et al.  Dynamic Metabolic Response to Adriamycin-Induced Senescence in Breast Cancer Cells , 2018, Metabolites.

[4]  I. Malami,et al.  5,6-dehydrokawain from the rhizome of Alpinia mutica Roxb. induced proangiogenic tumour-derived VEGF of HT-29 colorectal cancer , 2018, Natural product research.

[5]  Y. Jeon,et al.  Apoptotic and antiproliferative effects of Stigmast-5-en-3-ol from Dendronephthya gigantea on human leukemia HL-60 and human breast cancer MCF-7 cells. , 2018, Toxicology in vitro : an international journal published in association with BIBRA.

[6]  Tao Chen,et al.  microRNA-129-5p suppresses Adriamycin resistance in breast cancer by targeting SOX2. , 2018, Archives of biochemistry and biophysics.

[7]  Ping Zhang,et al.  TGF-β plays a vital role in triple-negative breast cancer (TNBC) drug-resistance through regulating stemness, EMT and apoptosis. , 2018, Biochemical and biophysical research communications.

[8]  S. Cho,et al.  Quercetin Suppresses CYR61-Mediated Multidrug Resistance in Human Gastric Adenocarcinoma AGS Cells , 2018, Molecules.

[9]  J. Shaik,et al.  In Vitro Screening of Three Indian Medicinal Plants for Their Phytochemicals, Anticholinesterase, Antiglucosidase, Antioxidant, and Neuroprotective Effects , 2017, BioMed research international.

[10]  B. Tekwani,et al.  Biological evaluation of phytoconstituents from Polygonum hydropiper , 2017, Natural product research.

[11]  Jing Xu,et al.  Metformin reverses prostate cancer resistance to enzalutamide by targeting TGF-β1/STAT3 axis-regulated EMT , 2017, Cell Death & Disease.

[12]  Shuang Huang,et al.  Triple negative breast cancer development can be selectively suppressed by sustaining an elevated level of cellular cyclic AMP through simultaneously blocking its efflux and decomposition , 2016, Oncotarget.

[13]  Y. Liu,et al.  Arctigenin inhibits STAT3 and exhibits anticancer potential in human triple-negative breast cancer therapy , 2016, Oncotarget.

[14]  Tsung-Ying Yang,et al.  Hypoxia can impair doxorubicin resistance of non-small cell lung cancer cells by inhibiting MRP1 and P-gp expression and boosting the chemosensitizing effects of MRP1 and P-gp blockers , 2016, Cellular Oncology.

[15]  M. Patankar,et al.  Modulation of oxidative stress and subsequent induction of apoptosis and endoplasmic reticulum stress allows citral to decrease cancer cell proliferation , 2016, Scientific Reports.

[16]  Y. Morimoto,et al.  5,6-Dehydrokawain from Alpinia zerumbet promotes osteoblastic MC3T3-E1 cell differentiation , 2016, Bioscience, biotechnology, and biochemistry.

[17]  J. Patel,et al.  Cellular Effect of Curcumin and Citral Combination on Breast Cancer Cells: Induction of Apoptosis and Cell Cycle Arrest , 2015, Journal of breast cancer.

[18]  Sung-Hoon Kim,et al.  Activation of Caspase‐9/3 and Inhibition of Epithelial Mesenchymal Transition are Critically Involved in Antitumor Effect of Phytol in Hepatocellular Carcinoma Cells , 2015, Phytotherapy research : PTR.

[19]  Annette Meeson,et al.  Epithelial-to-mesenchymal transition: what is the impact on breast cancer stem cells and drug resistance. , 2014, Cancer treatment reviews.

[20]  M. Taheri,et al.  MRP1 but Not MDR1 Is Associated with Response to Neoadjuvant Chemotherapy in Breast Cancer Patients , 2013, Disease markers.

[21]  K. Horgan,et al.  Neoadjuvant Chemotherapy Induces Expression Levels of Breast Cancer Resistance Protein That Predict Disease-Free Survival in Breast Cancer , 2013, PloS one.

[22]  D. Dodwell,et al.  Breast cancer subtypes: response to radiotherapy and potential radiosensitisation. , 2013, The British journal of radiology.

[23]  Rafał Matkowski,et al.  ABCC2 (MRP2, cMOAT) Localized in the Nuclear Envelope of Breast Carcinoma Cells Correlates with Poor Clinical Outcome , 2012, Pathology & Oncology Research.

[24]  Fazlul H. Sarkar,et al.  Cancer Stem Cells and Epithelial-to-Mesenchymal Transition (EMT)-Phenotypic Cells: Are They Cousins or Twins? , 2011, Cancers.

[25]  K. Sim,et al.  Phytochemical and Cytotoxic Investigations of Alpinia mutica Rhizomes , 2011, Molecules.

[26]  Jorge S Reis-Filho,et al.  Triple-negative breast cancer. , 2010, The New England journal of medicine.

[27]  Charles M Perou,et al.  Molecular stratification of triple-negative breast cancers. , 2010, The oncologist.

[28]  M. Stuschke,et al.  Use of γH2AX and other biomarkers of double-strand breaks during radiotherapy. , 2010, Seminars in radiation oncology.

[29]  Raghu Kalluri,et al.  The basics of epithelial-mesenchymal transition. , 2009, The Journal of clinical investigation.

[30]  R. Weinberg,et al.  Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits , 2009, Nature Reviews Cancer.

[31]  Gerhard Christofori,et al.  EMT, the cytoskeleton, and cancer cell invasion , 2009, Cancer and Metastasis Reviews.

[32]  R. Schrecengost,et al.  A novel association between p130Cas and resistance to the chemotherapeutic drug adriamycin in human breast cancer cells. , 2008, Cancer research.

[33]  Ting-Chao Chou,et al.  Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies , 2006, Pharmacological Reviews.

[34]  C. Choi,et al.  ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal , 2005, Cancer Cell International.

[35]  G. Salvesen,et al.  Mechanisms of caspase activation. , 2003, Current opinion in cell biology.

[36]  S. Mandal,et al.  Evaluation of anti‐inflammatory potential of Pavetta indica Linn. leaf extract (family: Rubiaceae) in rats , 2003, Phytotherapy research : PTR.

[37]  J. Foekens,et al.  RNA expression of breast cancer resistance protein, lung resistance-related protein, multidrug resistance-associated proteins 1 and 2, and multidrug resistance gene 1 in breast cancer: correlation with chemotherapeutic response. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[38]  Z. Herceg,et al.  Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. , 2001, Mutation research.

[39]  O. Cozar,et al.  Comparative analysis of some active principles of herb plants by GC/MS. , 2000, Talanta.

[40]  A. Tandon,et al.  Isolation and characterization of an adriamycin-resistant breast tumor cell line , 1990, In Vitro Cellular & Developmental Biology.

[41]  M. Thabrew,et al.  A Comparative Study of the Efficacy of Pavetta indica and Osbeckia octandra in the Treatment of Liver Dysfunction , 1987, Planta medica.

[42]  T. Mosmann.  Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.

[43]  Jinming Gao,et al.  Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. , 2014, Critical reviews in eukaryotic gene expression.

[44]  Christine Unger,et al.  In vitro cell migration and invasion assays. , 2013, Mutation research.

[45]  G. Bisht,et al.  Chemical Composition of the Essential Oil of Pavetta indica L. Leaves , 2011 .

[46]  M. Jiang,et al.  p53 independent G1 arrest and apoptosis induced by adriamycin. , 1997, Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih.

[47]  C. H. Lin,et al.  Antiplatelet action of dehydrokawain derivatives isolated from Alpinia speciosa rhizoma. , 1990, The Chinese journal of physiology.

[48]  B. Sastri.  The Wealth of India. A Dictionary of Indian Raw Materials and Industrial Products. Raw Materials. , 1950 .