Investigational New Drugs

, Volume 26, Issue 6, pp 505–516 | Cite as

Modulation of key signal transduction molecules by a novel peptide combination effective for the treatment of gastrointestinal carcinomas

  • Anu T. SinghEmail author
  • Manu Jaggi
  • Sudhanand Prasad
  • Sarjana Dutt
  • Gurvinder Singh
  • Kakali Datta
  • Praveen Rajendran
  • Vinod K. Sanna
  • Rama Mukherjee
  • Anand C. Burman


We have reported earlier a novel combination of four structurally designed synthetic neuropeptide analogs of vasoactive intestinal peptide (VIP), bombesin, substance P and somatostatin, code-named DRF 7295 which have anti-tumor efficacy for adenocarcinomas in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). The discovery, synthesis, in vitro and in vivo efficacy was reported (Jaggi et al., Invest New Drugs, 2008). Gastrointestinal tumor cells of the colon, pancreas and duodenum were found to most sensitive to DRF7295 in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). We have further investigated and report here the modulation of cellular signaling in gastrointestinal carcinomas by DRF 7295, which may be mediating its observed anticancer activity in these cancer types. DRF 7295 inhibits the binding of specific neuropeptides initiating a cascade of cellular signaling events leading to programmed cell death. It down regulates the second messenger cAMP, epidermal growth factor (EGF) dependent proliferation and the phosphorylated MAP Kinase pERK1/2 in gastrointestinal carcinomas, thus depriving the tumour cells of critical pro-proliferative cellular signals. It triggers bcl2 and Caspase 3 dependent apoptotic cell death and induces p53 tumor suppressor protein in the treated carcinoma cells in vitro. It has significant anti-angiogenic potential as reflected in the inhibition of tube like formation in the endothelial cells and down regulation of VEGF levels. Tumour xenograft studies confirmed the in vivo efficacy of DRF 7295 for gastrointestinal carcinomas (Jaggi et al., Invest New Drugs, 2008). The Phase I clinical trials have shown DRF 7295 to be well tolerated and devoid of systemic toxicities of the conventional cytotoxics (Mukherjee et al., Phase I dose escalating study of DRF7295: a new class of peptide based drugs. “Abstract” ASCO ID:948, 2003). The drug may have a promising role in disease stabilization in colorectal and other cancers. Thus DRF 7295 is a novel targeted drug in the class of signal transduction modulators, with potential for treatment of gastrointestinal carcinomas.


Neuropeptide Gastrointestinal carcinomas Signaling Programmed cell death Targeted drug 



This project was partly funded by Department of Science and Technology, Ministry of Science, Government of India.

We acknowledge the valuable inputs and the editing of the manuscript by Dr. Ritu Verma and Ms Alka Madaan post doc and research scientist respectively in the lab during the writing of the manuscript.


  1. 1.
    Reubi JC (2003) Peptide Receptors as molecular targets for cancer diagnosis and therapy. Endocr Rev 24:389–427PubMedCrossRefGoogle Scholar
  2. 2.
    Jaggi M, Prasad S, Singh AT, Praveen R, Dutt S, Mathur A, Sharma R, Gupta N, Ahuja R, Mukherjee R, Burman AC (2008) Anticancer activity of a peptide combination in Gastrointestinal cancers targeting multiple neuropeptide receptors. Invest New Drugs. DOI  10.1007/s10637-008-9117-4
  3. 3.
    Corda D, Incalci MD (1997) Cell signaling and cancer treatment. Ann Oncol 8:429–433PubMedCrossRefGoogle Scholar
  4. 4.
    Sporn MB, Todaro GJ (1980) Autocrine secretion and malignant transformation of cells. N Engl J Med 303:378–389CrossRefGoogle Scholar
  5. 5.
    Reubi JC, Laderach U, Waser B, Gebbers JO, Robberecht P, Laissue JA (2000) Vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor subtypes in human tumours and their tissues of origin. Cancer Res 60:3105–3112PubMedGoogle Scholar
  6. 6.
    Reubi JC, Wenger S, Maurer JS, Schaer JC, Gugger M (2002) Bombesin receptor subtypes in human cancers: detection with the universal radioligand 125I-(D-Tyr6, {beta}-ALA11, PHE13, NLE14) Bombesin (6–14). Clin Cancer Res 8:1139–1146PubMedGoogle Scholar
  7. 7.
    Weckbecker G, Lewis I, Albert R, Schmid HA, Hoyer D, Bruns C (2003) Opportunities in somatostatin research: biological, chemical and therapeutic aspects. Nat Rev Drug Discov 2:999–1017PubMedCrossRefGoogle Scholar
  8. 8.
    Frucht H, Gazdar AF, Park JA, Jensen RT (1992) Characterization of functional receptors for gastrointestinal hormones on human colon cancer cells. Cancer Res 52:1114–1122PubMedGoogle Scholar
  9. 9.
    Pimentel E (1994) Growth factors and neoplasia. In: Handbook of growth factors: general basic aspects, vol. 1. CRC Press, USA, pp 329–337Google Scholar
  10. 10.
    Arteaga CL (2002) Epidermal growth factor receptor dependence in human tumours: more than just expression. Oncologist 7:31–39PubMedCrossRefGoogle Scholar
  11. 11.
    Van Zoelen EJ, Lenferink AE, Kramer RH, Van de Poll ML (1996) Rational design for the development of epidermal growth factor receptor antagonists. Pathol Res Pract 192:761–767PubMedGoogle Scholar
  12. 12.
    Salomon DS, Brandt R, Ciardiello F, Normanno N (1995) Epidermal growth factor related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19:183–232PubMedCrossRefGoogle Scholar
  13. 13.
    Heasley LE (2001) Autocrine and paracrine signaling through neuropeptide receptors in human cancers. Oncogene 20:1563–1569PubMedCrossRefGoogle Scholar
  14. 14.
    Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signaling network. Nat Rev Mol Cell Biol 2:127–137PubMedCrossRefGoogle Scholar
  15. 15.
    Garrington TP, Johnson GL (1999) Organization and regulation of mitogen-activated protein kinase signaling pathways. Cur Opin Cell Biol 1999 11:211–218CrossRefGoogle Scholar
  16. 16.
    Ostrowski J, Trzeciak L, Kolodziejski J, Bomsztyk K (1997) Increased constitutive activity of mitogen-activated protein kinase and renaturable 85 kDa kinase in human colorectal cancer. Br J Cancer 78:1301–1306Google Scholar
  17. 17.
    Wyllie AH (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284:555–556PubMedCrossRefGoogle Scholar
  18. 18.
    Peled A, Zipori D, Rotter V (1996) Cooperation between p53 dependant and p53 independent apoptotic pathways in myeloid cells. Cancer Res 56:2148–2156PubMedGoogle Scholar
  19. 19.
    Kirsch DG, Kastan MB (1998) Tumour suppressor p53: implications for tumour development and prognosis. J Clin Oncol 16:3158–3168PubMedGoogle Scholar
  20. 20.
    Reed JC, Miyashita T, Takayama S, Wang HG, Sato T, Krajewski S, Aime-Seme C, Bodrug S, Kitada S, Hanada M (1996) Bcl-2 family proteins: regulators of cell death involved in the pathogenesis of cancer. J Cell Biochem 60:23–32PubMedCrossRefGoogle Scholar
  21. 21.
    Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic phenomenon and wide ranging implications in tissue kinetics. Br J Cancer 26:239–257PubMedGoogle Scholar
  22. 22.
    Earnshaw WC, Martins L, Kaufmann SH (1999) Mammalian caspases: structure, activation, substrates and functions during apoptosis. Ann Rev Biochem 68:383–424PubMedCrossRefGoogle Scholar
  23. 23.
    Wolf BB, Green DR (1999) Suicidal tendencies: apoptotic cell dearth by caspase family proteases. J Biol Chem 274:20049–20052PubMedCrossRefGoogle Scholar
  24. 24.
    Danesi R, Del TM (1996) The effects of the somatostatin analogue ocreotide on angiogenesis in vitro. Metabolism 45:49–50PubMedCrossRefGoogle Scholar
  25. 25.
    Woltering EA, Barrie R, O’Dorisio TM, Arce D, Ure T, Cramer A, Holmes D, Robertson J, Fassler J (1991) Somatostatin analogues inhibit angiogenesis in the chick chorioallantoic membrane. J Surg Res 50:245–251PubMedCrossRefGoogle Scholar
  26. 26.
    Dasgupta P (2004) Somatostatin analogues: multiple roles in cellular proliferation, neoplasia and angiogenesis. Pharmacol Ther 102:61–85PubMedCrossRefGoogle Scholar
  27. 27.
    Levine L, Lucci JA 3rd, Pazdrak B, Cheng JZ, Guo YS, Townsend TM, Hellmich MR (2003) Bombesin stimulates nuclear factor kB activation and expression of proangiogenic factors in prostate cancer cells. Cancer Res 63:3495–3502PubMedGoogle Scholar
  28. 28.
    Collado B, Canas IG, Henche NR, Prieto JC, Carmena MJ (2004) Vasoactive intestinal peptide increases vascular endothelial growth factor expression and neuroendocrine differentiation in human prostate cancer LNCAP cells. Regulatory Pept 119:69–75CrossRefGoogle Scholar
  29. 29.
    Mukherjee R, Jaggi M: Drug for treatment of cancer. US Patent 6,156,725Google Scholar
  30. 30.
    Mukherjee R, Jaggi M, Prasad S, Burman AC, Praveen R, Mathur A, Singh AT: Antiangogenic drugs. US Patent 6,492,330Google Scholar
  31. 31.
    Burman AC, Prasad S, Mukherjee R, Jaggi M, Singh AT, Mathur A: Somatostatin analogs for the treatment of cancer. US Patent 6,316,414Google Scholar
  32. 32.
    Burman AC, Prasad S, Mukherjee R, Jaggi M, Singh AT, Sharma R: Peptides for the treatment of cancer. US Patent 6,828,304Google Scholar
  33. 33.
    Burman AC, Prasad S, Mukherjee R, Jaggi M, Singh AT: Substance P analogs for the treatment of cancer. US Patent 6,596,692Google Scholar
  34. 34.
    Szapeshazi K, Schally AV, Nagy A, Wagner BW, Bajo AM, Halmos G (2003) Preclinical evaluation of therapeutic effects of targeted cytotoxic analogs of somatostatin and bombesin on human gastric carcinomas. Cancer 98:1401–1410CrossRefGoogle Scholar
  35. 35.
    Stangelberger A, Schally AV, Varga JL, Hammann BD, Groot K, Halmos G, Cai RZ, Zarandi M (2005) Antagonists of growth hormone releasing hormone (GHRH) and of bombesin/gastrin releasing peptide (BN/GRP) suppress the expression of VEGF, bFGF and receptors of the EGF/HER family in PC-3 and DU 145 human androgen independent prostate cancers. Prostate 64:303–315PubMedCrossRefGoogle Scholar
  36. 36.
    Guha S, Eibl G, Kisfalvi K, Fan RS, Burdick M, Reber H, Hines OJ, Strieter R, Rozengurt E (2005) Broad spectrum G protein coupled receptor antagonist (d-Arg, d-Trp 5,7, 9, Leu 11) SP: a dual inhibitor of growth and angiogenesis in pancreatic cancer. Cancer Res 65:2738–2745PubMedCrossRefGoogle Scholar
  37. 37.
    Dumont JE, Jauniax JC, Roger PP (1989) The cAMP mediated stimulation of cell proliferation. Trends Biochem Sci 14:67–71PubMedCrossRefGoogle Scholar
  38. 38.
    Reisine T, Woulfe D, Raynor K, Kong H, Heerding J, Hines J (1995) Interaction of somatostatin receptors with G-proteins and cellular effector systems. In: Chadwick DJ, Cardew G (eds) Somatostatin and its receptors, vol 162. Wiley, New York, pp 160–170CrossRefGoogle Scholar
  39. 39.
    Fulda S, Susin SA, Kroemer G, Debatin KM (1998) Molecular ordering of apoptosis induced by anticancer drugs in neuroblastoma cells. Cancer Res 58:4453–4460PubMedGoogle Scholar
  40. 40.
    Qin Y, Ertl T, Groot K, Horvath J, Cai RZ, Schally AV (1995) Somatostatin analog C-160 inhibits growth of CFPAC-1 human pancreatic carcinoma cells in vitro and intracellular production of cAMP. Int J Cancer 60:694–700PubMedCrossRefGoogle Scholar
  41. 41.
    Sharma K, Srikant CB (1998) Induction of wild-type p53, Bax, and acidic endonuclease during somatostatin-signaled apoptosis in MCF-7 human breast cancer cells. Int J Cancer 76:259–266PubMedCrossRefGoogle Scholar
  42. 42.
    Matsumoto Y, Kawatani M, Simizu S, Tanaka T, Takada M, Imoto M (2000) Bcl-2-independent induction of apoptosis by neuropeptide receptor antagonist in human small cell lung carcinoma cells. Anticancer Res 20:3123–3129PubMedGoogle Scholar
  43. 43.
    Tallet A, Chilvers ER, Hannah S, Dransfield I, Lawson MF, Haslett C, Sethi T (1996) Inhibition of neuropeptide-stimulated tyrosine phosphorylation and tyrosine kinase activity stimulates apoptosis in small cell lung cancer cells. Cancer Res 56:4255–4263Google Scholar
  44. 44.
    Mukherjee R, Doval D C, Raghunadharao D, Majumdar A, Ganguly S, Jaggi M, Prasad S, Singh AT, Burman AC (2003) Phase I dose escalating study of DRF7295: A new class of peptide based drugs. “Abstract” ASCO ID:948Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Anu T. Singh
    • 1
    Email author
  • Manu Jaggi
    • 1
  • Sudhanand Prasad
    • 1
  • Sarjana Dutt
    • 1
  • Gurvinder Singh
    • 1
  • Kakali Datta
    • 1
  • Praveen Rajendran
    • 1
  • Vinod K. Sanna
    • 1
  • Rama Mukherjee
    • 1
  • Anand C. Burman
    • 1
  1. 1.Dabur Research FoundationGhaziabadIndia

Personalised recommendations