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Apoptosis induction by an analog of curcumin (BDMC-A) in human laryngeal carcinoma cells through intrinsic and extrinsic pathways

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Abstract

Background

Head and neck cancer is the sixth most frequently occurring cancer worldwide and accounts for about 2 % of all cancer-related deaths annually. Curcumin is a well-known chemopreventive agent, and apoptosis induction by curcumin has been reported in many cancer cell types. We synthesized an ortho-hydroxy substituted analog of curcumin, bisdemethoxycurcumin analog (BDMC-A), and aimed to demarcate the apoptotic effects induced by BDMC-A on human laryngeal cancer Hep-2 cells and to compare these effects with those induced by curcumin.

Methods

We evaluated the apoptotic effects of BDMC-A in comparison to those of curcumin on Hep-2 cells by performing Western blotting, RT-PCR, fluorescent staining and DNA fragmentation assays. In addition, we carried out an in silico molecular docking study on the EGFR kinase domain.

Results

We found that BDMC-A can induce apoptosis in Hep-2 cells by regulating the expression of both intrinsic and extrinsic apoptotic proteins, i.e., Bcl-2, Bax, apoptososme complex and death receptors, more efficiently than curcumin. We also observed increased nuclear fragmentation and chromatin condensation after BDMC-A treatment compared to curcumin treatment. Depolarized mitochondria and ROS generation was well pronounced in both BDMC-A and curcumin treated Hep-2 cells. Our in silico molecular docking study on the EGFR kinase domain revealed that BDMC-A may dock more efficiently than curcumin.

Conclusions

From our results we conclude that BDMC-A can induce apoptosis in Hep-2 laryngeal carcinoma cells more effectively than curcumin, and that this activity can be attributed to the presence of a hydroxyl group at the ortho position within this compound.

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References

  1. S. Ghosh, A. Ghosh, G.P. Maiti, N. Alam, A. Roy, B. Roy, S. Roychoudhury, C.K. Panda, Alterations of 3p21.31 tumor suppressor genes in head and neck squamous cell carcinoma: correlation with progression and prognosis. Int. J. Cancer 123, 2594–2604 (2008)

    Article  CAS  PubMed  Google Scholar 

  2. C. Salazar, R. Nagadia, P. Pandit, J. Cooper-White, N. Banerjee, N. Dimitrova, W.B. Coman, C. Punyadeera, A novel saliva-based microRNA biomarker panel to detect head and neck cancers. Cell. Oncol. 37, 331–338 (2014)

    Article  CAS  Google Scholar 

  3. T. Nakaoka, A. Ota, T. Ono, S. Karnan, H. Konishi, A. Furuhashi, Y. Ohmura, Y. Yamada, Y. Hosokawa, Y. Kazaoka, Combined arsenic trioxide-cisplatin treatment enhances apoptosis in oral squamous cell carcinoma cells. Cell. Oncol. 37, 119–129 (2014)

    Article  CAS  Google Scholar 

  4. D. Weiss, C. Stockmann, K. Schrödter, C. Rudack, Protein expression and promoter methylation of the candidate biomarker TCF21 in head and neck squamous cell carcinoma. Cell. Oncol. 36, 213–224 (2013)

    Article  CAS  Google Scholar 

  5. B.B. Aggarwal, C. Sundaram, N. Malani, H. Ichikawa, Curcumin: the Indian solid gold. Adv. Exp. Med. Biol. 595, 1–75 (2007)

    Article  PubMed  Google Scholar 

  6. S. Shishodia, M.M. Chaturvedi, B.B. Aggarwal, Role of curcumin in cancer therapy. Curr. Probl. Cancer 31, 243–305 (2007)

    Article  PubMed  Google Scholar 

  7. N. Chakravarti, J.N. Myers, B.B. Aggarwal, Targeting constitutive and interleukin-6-inducible signal transducers and activators of transcription 3 pathway in head and neck squamous cell carcinoma cells by curcumin (diferuloylmethane). Int. J. Cancer 119, 1268–1275 (2006)

    Article  CAS  PubMed  Google Scholar 

  8. A. Chen, J. Xu, A.C. Johnson, Curcumin inhibits human colon cancer cell growth by suppressing gene expression of epidermal growth factor receptor through reducing the activity of the transcription factor Egr-1. Oncogene 25, 278–287 (2006)

    PubMed  Google Scholar 

  9. S. Prakobwong, J. Khoontawad, P. Yongvanit, C. Pairojkul, Y. Hiraku, P. Sithithaworn, P. Pinlaor, B.B. Aggarwal, S. Pinlaor, Curcumin decreases cholangiocarcinogenesis in hamsters by suppressing inflammation-mediated molecular events related to multistep carcinogenesis. Int. J. Cancer 129, 88–100 (2011)

    Article  CAS  PubMed  Google Scholar 

  10. P. Anand, C. Sundaram, S. Jhurani, A.B. Kunnumakkara, B.B. Aggarwal, Curcumin and cancer: an “old-age” disease with an “age-old” solution. Cancer Lett. 267, 133–164 (2008)

    Article  CAS  PubMed  Google Scholar 

  11. J.M. Davis, E.A. Murphy, M.D. Carmichael, M.R. Zielinski, C.M. Groschwitz, A.S. Brown, J.D. Gangemi, A. Ghaffar, E.P. Mayer, Curcumin effects on inflammation and performance recovery following eccentric exercise-induced muscle damage. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, 2168–2173 (2007)

    Article  Google Scholar 

  12. B.B. Aggarwal, A. Kumar, A.C. Bharti, Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res. 23, 363–398 (2003)

    CAS  PubMed  Google Scholar 

  13. J. Nautiyal, S. Banerjee, S.S. Kanwar, Y. Yu, B.B. Patel, F.H. Sarkar, A.P. Majumdar, Curcumin enhances dasatinib-induced inhibition of growth and transformation of colon cancer cells. Int. J. Cancer 128, 951–961 (2011)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. R.J. Anto, G. Kuttan, K.V.D. Babu, K.V. Rajasekharan, R. Kuttan, Anti-tumour and free radical scavenging activity of synthetic curcuminoids. Inter. J. Pharm. 131, 1–7 (1996)

    Article  CAS  Google Scholar 

  15. R.J. Anto, J. George, K.V. Babu, K.N. Rajasekharan, R. Kuttan, Antimutagenic and anticarcinogenic activity of natural and synthetic curcuminoid. Mutat. Res. 370, 127–131 (1996)

    Article  CAS  PubMed  Google Scholar 

  16. R. Rukkumani, K. Aruna, P.S. Varma, K.N. Rajasekaran, V.P. Menon, Comparative effects of curcumin and an analog of curcumin on alcohol and PUFA induced oxidative stress. J. Pharm. Pharm. Sci. 7, 274–283 (2004)

    CAS  PubMed  Google Scholar 

  17. R. Rukkumani, K. Aruna, P.S. Varma, P. Viswanathan, K.N. Rajasekaran, V.P. Menon, Protective role of a novel curcuminoid on alcohol and PUFA-induced hyperlipidemia. Toxicol. Mech. Methods 15, 227–234 (2005)

    Article  CAS  PubMed  Google Scholar 

  18. R. Rajagopalan, S. Sridharan, V.P. Menon, Hepatoprotective role of bis-demethoxy curcumin analog on the expression of matrix metalloproteinase induced by alcohol and polyunsaturated fatty acid in rats. Toxicol. Mech. Methods 20, 252–259 (2010)

    Article  CAS  PubMed  Google Scholar 

  19. T. Devasena, K.N. Rajasekaran, V.P. Menon, Bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione (a curcumin analog) ameliorates DMH-induced hepatic oxidative stress during colon carcinogenesis. Pharmacol. Res. 46, 39–45 (2002)

    Article  CAS  PubMed  Google Scholar 

  20. M. Kumaravel, P. Sankar, P. Latha, C.S. Benson, R. Rukkumani, Antiproliferative effects of an analog of curcumin in Hep-2 cells: a comparative study with curcumin. Nat. Prod. Commun. 8, 183–186 (2013)

    CAS  PubMed  Google Scholar 

  21. K.Y. Chang, S.Y. Tsai, S.H. Chen, H.H. Tsou, C.J. Yen, K.J. Liu, H.L. Fang, H.C. Wu, B.F. Chuang, S.W. Chou, C.K. Tang, S.Y. Liu, P.J. Lu, C.Y. Yen, J.Y. Chang, Dissecting the EGFR-PI3K-AKT pathway in oral cancer highlights the role of the EGFR variant III and its clinical relevance. J. Biomed. Sci. 20, 43 (2013)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. S. Haupt, M. Berger, Z. Goldberg, Y. Haupt, Apoptosis - the p53 network. J. Cell Sci. 116, 4077–4085 (2003)

    Article  CAS  PubMed  Google Scholar 

  23. G. Sa, T. Das, Anti cancer effects of curcumin: cycle of life and death. Cell Div. 3, 14 (2008)

    Article  PubMed Central  PubMed  Google Scholar 

  24. C. Gajate, F. Mollinedo, Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy. J. Biol. Chem. 280, 11641–11647 (2005)

    Article  CAS  PubMed  Google Scholar 

  25. H.F. Lu, K.C. Lai, S.C. Hsu, H.J. Lin, M.D. Yang, Y.L. Chen, M.J. Fan, J.S. Yang, P.Y. Cheng, C.L. Kuo, J.G. Chung, Curcumin induces apoptosis through FAS and FADD, in caspase-3-dependent and -independent pathways in the N18 mouse-rat hybrid retina ganglion cells. Oncol. Rep. 22, 97–104 (2009)

    CAS  PubMed  Google Scholar 

  26. S. Shankar, R.K. Srivastava, Bax and Bak genes are essential for maximum apoptotic response by curcumin, a polyphenolic compound and cancer chemopreventive agent derived from turmeric, Curcuma longa. Carcinog. 28, 1277–1286 (2007)

    Article  CAS  Google Scholar 

  27. M. Roy, S. Chakraborty, M. Siddiqi, R.K. Bhattacharya, Induction of Apoptosis in Tumor Cells by Natural Phenolic Compounds. Asian Pac. J. Cancer Prev. 3, 61–67 (2002)

    PubMed  Google Scholar 

  28. K.V. Dinesh Babu, K.N. Rajasekaran, Simplified conditions for the synthesis of curcumin I and other curcuminoids. Org. Prep. Proc. Int. 24, 674–677 (1994)

    Article  Google Scholar 

  29. R.J. Fido, A.S. Tatham, P.R. Shewry, Western blotting analysis, in Methods in molecular biology: plant gene transfer and expression protocols, ed. by H. Jones, vol. 49 (Humana Press Inc, Totowa, 1995), pp. 423–437

    Google Scholar 

  30. P. Chomczynski, N. Sacchi, Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159 (1987)

    Article  CAS  PubMed  Google Scholar 

  31. C. Brana, C. Benham, L. Sundstrom, A method for characterising cell death in vitro by combining propidium iodide staining with immunohistochemistry. Brain Res. Brain Res. Protoc. 10, 109–114 (2002)

    Article  CAS  PubMed  Google Scholar 

  32. R.A. Friesner, R.B. Murphy, M.P. Repasky, L.L. Frye, J.R. Greenwood, T.A. Halgren, P.C. Sanschagrin, D.T. Mainz, Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem. 4, 6177–6196 (2006)

    Article  Google Scholar 

  33. D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011)

    Article  CAS  PubMed  Google Scholar 

  34. C. Ramachandran, S. Rodriguez, R. Ramachandran, P.K. Raveendran Nair, H. Fonseca, Z. Khatib, E. Escalon, S.J. Melnick, Expression profiles of apoptotic genes induced by curcumin in human breast cancer and mammary epithelial cell lines. Anticancer Res. 25, 3293–3302 (2005)

    CAS  PubMed  Google Scholar 

  35. S.W. Lowe, E. Cepero, G. Evan, Intrinsic tumour suppression. Nature 432, 307–315 (2004)

    Article  CAS  PubMed  Google Scholar 

  36. T. Miyashita, J.C. Reed, Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80, 293–299 (1995)

    Article  CAS  PubMed  Google Scholar 

  37. S. Awantika, K. Durga Prasad, G. Archana, In Silico molecular docking analysis to identify PI3K inhibitors as possible NSCLC agents. Int. J. Comput. Bioinfo. In Silico Model 2, 68–71 (2013)

    Google Scholar 

  38. U.M. Moll, O. Petrenko, The MDM2-p53 interaction. Mol. Cancer Res. 1, 1001–1008 (2003)

    CAS  PubMed  Google Scholar 

  39. R. Wilken, M.S. Veena, M.B. Wang, E.S. Srivatsan, Curcumin: a review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma. Mol. Cancer 10, 12 (2011)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. S. Shankar, Q. Chen, K. Sarva, I. Siddiqui, R.K. Srivastava, Curcumin enhances the apoptosis-inducing potential of TRAIL in prostate cancer cells: molecular mechanisms of apoptosis, migration and angiogenesis. J. Mol. Signal. 2, 10 (2007)

    Article  PubMed Central  PubMed  Google Scholar 

  41. R.U. Janicke, M.L. Sprengart, M.R. Wati, A.G. Porter, Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J. Biol. Chem. 273, 9357–9360 (1998)

    Article  CAS  PubMed  Google Scholar 

  42. H.Y. Chang, X. Yang, Proteases for cell suicide: functions and regulation of caspases. Microbiol. Mol. Biol. Rev. 64, 821–846 (2000)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. R. Prasanna, C.C. Harish, R. Pichai, D. Sakthisekaran, P. Gunasekaran, Anti-cancer effect of Cassia auriculata leaf extract in vitro through cell cycle arrest and induction of apoptosis in human breast and larynx cancer cell lines. Cell Biol. Int. 33, 127–134 (2009)

    Article  CAS  PubMed  Google Scholar 

  44. C.B. Gonzales, N.B. Kirma, J.J. De La Chapa, R. Chen, M.A. Henry, S. Luo, K.M. Hargreaves, Vanilloids induce oral cancer apoptosis independent of TRPV1. Oral Oncol. 50, 437–447 (2014)

    Article  CAS  PubMed  Google Scholar 

  45. D. Wang, J. Hu, L. Lv, X. Xia, J. Liu, X. Li, Enhanced inhibitory effect of curcumin via reactive oxygen species generation in human nasopharyngeal carcinoma cells following purple-light irradiation. Oncol. Lett. 6, 81–85 (2013)

    PubMed Central  PubMed  Google Scholar 

  46. A. Shehzad, J. Lee, T.L. Huh, Y.S. Lee, Curcumin induces apoptosis in human colorectal carcinoma (HCT-15) cells by regulating expression of Prp4 and p53. Mol. Cells 35, 526–532 (2013)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. T. Atsumi, K. Tonosaki, S. Fujisawa, Induction of early apoptosis and ROS-generation activity in human gingival fibroblasts (HGF) and human submandibular gland carcinoma (HSG) cells treated with curcumin. Arch. Oral Biol. 51, 913–921 (2006)

    Article  CAS  PubMed  Google Scholar 

  48. N. Hasima, B.B. Aggarwal, Cancer-linked targets modulated by curcumin. Int. J. Biochem. Mol. Biol. 3, 328–351 (2012)

    CAS  PubMed Central  PubMed  Google Scholar 

  49. S. Shishodia, Molecular mechanisms of curcumin action: gene expression. Biofactors 39, 37–55 (2013)

    Article  CAS  PubMed  Google Scholar 

  50. G.P. Maiti, P. Mondal, N. Mukherjee, A. Ghosh, S. Ghosh, S. Dey, J. Chakrabarty, A. Roy, J. Biswas, S. Roychoudhury, C.K. Panda, Overexpression of EGFR in head and neck squamous cell carcinoma is associated with inactivation of SH3GL2 and CDC25A genes. PLoS One 8, e63440 (2013)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. J. Stamos, M.X. Sliwkowski, C. Eigenbrot, Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J. Biol. Chem. 277, 46265–46272 (2002)

    Article  CAS  PubMed  Google Scholar 

  52. R.B. Cohen, Current challenges and clinical investigations of epidermal growth factor receptor (EGFR) - and ErbB family-targeted agents in the treatment of head and neck squamous cell carcinoma (HNSCC). Cancer Treat. Rev. 40, 567–577 (2014)

    Article  CAS  PubMed  Google Scholar 

  53. M.E. Noble, J.A. Endicott, L.N. Johnson, Protein kinase inhibitors: insights into drug design from structure. Science 303, 1800–1805 (2004)

    Article  CAS  PubMed  Google Scholar 

  54. J.J. Liao, Molecular recognition of protein kinase binding pockets for design of potent and selective kinase inhibitors. J. Med. Chem. 50, 409–424 (2007)

    Article  CAS  PubMed  Google Scholar 

  55. Y.H. Peng, H.Y. Shiao, C.H. Tu, P.M. Liu, J.T. Hsu, P.K. Amancha, J.S. Wu, M.S. Coumar, C.H. Chen, S.Y. Wang, W.H. Lin, H.Y. Sun, Y.S. Chao, P.C. Lyu, H.P. Hsieh, S.Y. Wu, Protein kinase inhibitor design by targeting the Asp-Phe-Gly (DFG) motif: the role of the DFG motif in the design of epidermal growth factor receptor inhibitors. J. Med. Chem. 56, 3889–3903 (2013)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was financially supported by University Grants Commission [F.No 37-309/2009(SR)] and UGC [F.No 41-981/2012 (SR)]. The authors thank DST-FIST, UGC-SAP and DBT -IPLS for providing the infrastructural support. Kumaravel Mohankumar thanks CSIR for providing a senior research fellowship.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Puducherry, 605014, India

    Kumaravel Mohankumar, Sankar Pajaniradje, Subhashree Sridharan, Latha Periyasamy & Rukkumani Rajagopalan

  2. Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry, 605014, India

    Vivek Kumar Singh & Mohane Selvaraj Coumar

  3. Virology Laboratory-II, National Institute of Immunology, New Delhi, India

    Larance Ronsard & Akhil C. Banerjea

  4. Department of Endocrinology, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Chennai, 600013, India

    Benson Chellakkan Selvanesan

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  1. Kumaravel Mohankumar
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Correspondence to Rukkumani Rajagopalan.

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Mohankumar, K., Pajaniradje, S., Sridharan, S. et al. Apoptosis induction by an analog of curcumin (BDMC-A) in human laryngeal carcinoma cells through intrinsic and extrinsic pathways. Cell Oncol. 37, 439–454 (2014). https://doi.org/10.1007/s13402-014-0207-3

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