5-O-Acetyl-Renieramycin T from Blue Sponge Xestospongia sp. Induces Lung Cancer Stem Cell Apoptosis

Lung cancer is one of the most significant cancers as it accounts for almost 1 in 5 cancer deaths worldwide, with an increasing incident rate. Management of the cancer has been shown to frequently fail due to the ability of the cancer cells to resist therapy as well as metastasis. Recent evidence has suggested that the poor response to the current treatment drugs and the ability to undergo metastasis are driven by cancer stem cells (CSCs) within the tumor. The discovery of novel compounds able to suppress CSCs and sensitize the chemotherapeutic response could be beneficial to the improvement of clinical outcomes. Herein, we report for the first time that 5-O-acetyl-renieramycin T isolated from the blue sponge Xestospongia sp. mediated lung cancer cell death via the induction of p53-dependent apoptosis. Importantly, 5-O-acetyl-renieramycin T induced the death of CSCs as represented by the CSC markers CD44 and CD133, while the stem cell transcription factor Nanog was also found to be dramatically decreased in 5-O-acetyl-renieramycin T-treated cells. We also found that such a CSC suppression was due to the ability of the compound to deplete the protein kinase B (AKT) signal. Furthermore, 5-O-acetyl-renieramycin T was able to significantly sensitize cisplatin-mediated apoptosis in the lung cancer cells. Together, the present research findings indicate that this promising compound from the marine sponge is a potential candidate for anti-cancer approaches.

[1]  N. Saito,et al.  Construction of the Pentacyclic Core and Formal Total Synthesis of (rac)‐Renieramycin T , 2018, ChemistryOpen.

[2]  Glauber C. Brito,et al.  Phosphorylation switches Bax from promoting to inhibiting apoptosis thereby increasing drug resistance , 2018, EMBO reports.

[3]  Wipa Chantarawong,et al.  Lung Cancer Stem Cells and Cancer Stem Cell-targeting Natural Compounds , 2018, AntiCancer Research.

[4]  Mei Li,et al.  Utilization of lung cancer cell lines for the study of lung cancer stem cells , 2018, Oncology letters.

[5]  T. S. Ramasamy,et al.  Cancer stem cells as key drivers of tumour progression , 2018, Journal of Biomedical Science.

[6]  Ita Novita Sari,et al.  Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment , 2018, Stem cells international.

[7]  Yue Yang,et al.  CD44 promotes cell proliferation in non-small cell lung cancer , 2018, Oncology letters.

[8]  Junfei Jin,et al.  Bcl-2 and Bcl-xL mediate resistance to receptor tyrosine kinase-targeted therapy in lung and gastric cancer , 2017, Anti-cancer drugs.

[9]  Ashish S. Bodhade,et al.  Cancer stem cells: An insight , 2017, Journal of oral and maxillofacial pathology : JOMFP.

[10]  P. Chanvorachote,et al.  Chemistry of Renieramycins. 17. A New Generation of Renieramycins: Hydroquinone 5-O-Monoester Analogues of Renieramycin M as Potential Cytotoxic Agents against Non-Small-Cell Lung Cancer Cells. , 2017, Journal of natural products.

[11]  W. Guo,et al.  Cisplatin-enriching cancer stem cells confer multidrug resistance in non-small cell lung cancer via enhancing TRIB1/HDAC activity , 2017, Cell Death & Disease.

[12]  V. Pongrakhananon,et al.  Suppression of cancer stem-like phenotypes in NCI-H460 lung cancer cells by vanillin through an Akt-dependent pathway. , 2017, International journal of oncology.

[13]  J. Hao,et al.  Targeting Signaling Pathways in Cancer Stem Cells for Cancer Treatment , 2017, Stem cells international.

[14]  H. Sasano,et al.  Bcl‐2 family in non‐small cell lung cancer: its prognostic and therapeutic implications , 2017, Pathology international.

[15]  Y. Ba,et al.  Apigenin enhances the cisplatin cytotoxic effect through p53-modulated apoptosis. , 2017, Oncology letters.

[16]  I. Singh,et al.  Tetrahydroisoquinolines in therapeutics: a patent review (2010-2015) , 2017, Expert opinion on therapeutic patents.

[17]  Robert M. Williams,et al.  Stereoselective Total Synthesis of (-)-Renieramycin T. , 2016, The Journal of organic chemistry.

[18]  K. O'Byrne,et al.  Lung cancer stem cells: The root of resistance. , 2016, Cancer letters.

[19]  W. Matsui.  Cancer stem cell signaling pathways , 2016, Medicine.

[20]  S. Luanpitpong,et al.  Nitric Oxide and Aggressive Behavior of Lung Cancer Cells. , 2015, Anticancer research.

[21]  Zhanguo Zhang,et al.  MAPK/ERK Activation Sensitizes MKN-28 Cells to Cisplatin-Induced Apoptosis , 2015 .

[22]  Martina Müller,et al.  p53 Family and Cellular Stress Responses in Cancer , 2014, Front. Oncol..

[23]  P. Tchounwou,et al.  Cisplatin in cancer therapy: molecular mechanisms of action. , 2014, European journal of pharmacology.

[24]  S. Goodison,et al.  Angiogenin promotes tumoral growth and angiogenesis by regulating matrix metallopeptidase-2 expression via the ERK1/2 pathway , 2014, Oncogene.

[25]  M. Nishimura,et al.  CD133 expression: a potential prognostic marker for non-small cell lung cancers , 2014, International Journal of Clinical Oncology.

[26]  V. Pongrakhananon,et al.  Acquired resistance to chemotherapy in lung cancer cells mediated by prolonged nitric oxide exposure. , 2013, Anticancer research.

[27]  H. Motaln,et al.  Lung cancer stem cells: a biological and clinical perspective , 2013, Cellular Oncology.

[28]  Yong-zhong Wu,et al.  CD133 silencing inhibits stemness properties and enhances chemoradiosensitivity in CD133-positive liver cancer stem cells. , 2013, International journal of molecular medicine.

[29]  K. O'Byrne,et al.  Generation and Characterisation of Cisplatin-Resistant Non-Small Cell Lung Cancer Cell Lines Displaying a Stem-Like Signature , 2013, PloS one.

[30]  M. Huang,et al.  Cisplatin selects for multidrug-resistant CD133+ cells in lung adenocarcinoma by activating Notch signaling. , 2013, Cancer research.

[31]  Michael V. Fiandalo,et al.  Caspase control: protagonists of cancer cell apoptosis. , 2012, Experimental oncology.

[32]  G. Concepcion,et al.  Chemistry of renieramycins. Part 13: Isolation and structure of stabilized renieramycin type derivatives, renieramycins W–Y, from Philippine blue sponge Xestospongia sp., pretreated with potassium cyanide , 2012 .

[33]  Xiaochu Yan,et al.  Nanog regulates self‐renewal of cancer stem cells through the insulin‐like growth factor pathway in human hepatocellular carcinoma , 2012, Hepatology.

[34]  Fang Yuan,et al.  Interferon regulatory factor 4 binding protein is a novel p53 target gene and suppresses cisplatin-induced apoptosis of breast cancer cells , 2012, Molecular Cancer.

[35]  L. Galluzzi,et al.  Molecular mechanisms of cisplatin resistance , 2012, Oncogene.

[36]  Y. Liu,et al.  Activation of ERK-p53 and ERK-mediated phosphorylation of Bcl-2 are involved in autophagic cell death induced by the c-Met inhibitor SU11274 in human lung cancer A549 cells. , 2012, Journal of pharmacological sciences.

[37]  Julian Downward,et al.  RAS Interaction with PI3K: More Than Just Another Effector Pathway. , 2011, Genes & cancer.

[38]  B. Zhou,et al.  Activation of β-catenin and Akt pathways by Twist are critical for the maintenance of EMT associated cancer stem cell-like characters , 2011, BMC Cancer.

[39]  James W. Tung,et al.  Non-Small Cell Lung Cancer Cells Expressing CD44 Are Enriched for Stem Cell-Like Properties , 2010, PloS one.

[40]  J. Waldrep,et al.  Increasing p53 protein sensitizes non-small cell lung cancer to paclitaxel and cisplatin in vitro. , 2010, Anticancer research.

[41]  F. Qiu,et al.  Activation of Akt and MAPK pathways enhances the tumorigenicity of CD133+ primary colon cancer cells. , 2010, Carcinogenesis.

[42]  I. Herr,et al.  CD133 is indicative for a resistance phenotype but does not represent a prognostic marker for survival of non‐small cell lung cancer patients , 2009, International journal of cancer.

[43]  L. Mariani,et al.  Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment , 2009, Proceedings of the National Academy of Sciences.

[44]  K. Suwanborirux,et al.  Chemistry of renieramycins. Part 7: Renieramycins T and U, novel renieramycin–ecteinascidin hybrid marine natural products from Thai sponge Xestospongia sp. ☆ , 2009 .

[45]  T. Owa,et al.  Chemistry of renieramycins. Part 8: synthesis and cytotoxicity evaluation of renieramycin M-jorunnamycin A analogues. , 2009, Bioorganic & medicinal chemistry.

[46]  D. Newman,et al.  Impact of natural products on developing new anti-cancer agents. , 2009, Chemical reviews.

[47]  P. Schultz,et al.  The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations , 2009, Proceedings of the National Academy of Sciences.

[48]  T. Molinski,et al.  Drug development from marine natural products , 2009, Nature Reviews Drug Discovery.

[49]  Alexei Vazquez,et al.  The genetics of the p53 pathway, apoptosis and cancer therapy , 2008, Nature Reviews Drug Discovery.

[50]  Anna E. Lokshin,et al.  Drug-Selected Human Lung Cancer Stem Cells: Cytokine Network, Tumorigenic and Metastatic Properties , 2008, PloS one.

[51]  M. Schuler,et al.  Targeting BCL‐2 family proteins to overcome drug resistance in non‐small cell lung cancer , 2007, International journal of cancer.

[52]  Michael F Clarke,et al.  The biology of cancer stem cells. , 2007, Annual review of cell and developmental biology.

[53]  K. Vousden,et al.  Coping with stress: multiple ways to activate p53 , 2007, Oncogene.

[54]  Eddie Reed,et al.  Molecular basis of cellular response to cisplatin chemotherapy in non-small cell lung cancer (Review). , 2004, Oncology reports.

[55]  K. Suwanborirux,et al.  Chemistry of renieramycins. Part 5. Structure elucidation of renieramycin-type derivatives O, Q, R, and S from thai marine sponge Xestospongia species pretreated with potassium cyanide. , 2004, Journal of natural products.

[56]  K. Suwanborirux,et al.  Chemistry of renieramycins. Part 3.(1) isolation and structure of stabilized renieramycin type derivatives possessing antitumor activity from Thai sponge Xestospongia species, pretreated with potassium cyanide. , 2003, Journal of natural products.

[57]  Robin M. Williams,et al.  Chemistry and biology of the tetrahydroisoquinoline antitumor antibiotics. , 2002, Chemical reviews.

[58]  P. Krammer,et al.  Upregulation of bcl‐2 is involved in the mediation of chemotherapy resistance in human small cell lung cancer cell lines , 2002, International journal of cancer.

[59]  Scott W. Lowe,et al.  Apoptosis A Link between Cancer Genetics and Chemotherapy , 2002, Cell.

[60]  N. Holbrook,et al.  Requirement for ERK Activation in Cisplatin-induced Apoptosis* , 2000, The Journal of Biological Chemistry.

[61]  E. Yazlovitskaya,et al.  Effect of Extracellular Signal-regulated Kinase on p53 Accumulation in Response to Cisplatin* , 2000, The Journal of Biological Chemistry.

[62]  P. Proksch,et al.  Bioactive isoquinoline quinone from an undescribed Philippine marine sponge of the genus Xestospongia , 1996 .