Skip to main content

Advertisement

SpringerLink
Log in

Enhanced killing of cervical cancer cells by combinations of methyl jasmonate with cisplatin, X or alpha radiation

  • PRECLINICAL STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Current therapies for treatment of advanced cervical cancer involve the use of cisplatin, often in combination with radiotherapy. These treatments do not lead to a high survival rate and furthermore, serious side effects are dose-limiting factors. Methyl jasmonate (MJ) was recently identified as potent and selective cytotoxic agent towards cervical cancer cells. In the present study we evaluated the effectiveness of combined treatments of MJ with cisplatin or X-irradiation on a variety of cervical cancer cells including SiHa, CaSki, HeLa and C33A. Cytotoxicity of alpha particles, emitted from 224Ra atoms, was also evaluated as a single agent and in combination with MJ. Cooperation between MJ and cisplatin in reducing cell viability (XTT assays) and survival (clonogenicity assays) was exhibited towards several cancer cell lines at a range of combination doses. MJ effectively cooperated also with X-ray irradiation, significantly lowering the radiation doses required to inhibit cell survival (ID50) of all tested cells lines. We show for the first time, that alpha irradiation selectively reduced cell viability and survival of cervical cancer cells. Lower doses of α irradiation were required as compared to X-irradiation to inhibit cell survival. Cooperation with MJ was demonstrated in part of the cancer cell lines. In conclusion, our studies point to α irradiation and MJ, novel anticancer agents, as potent candidates for treatment of cervical cancer, in single agent regiments and in combination. MJ can be added also to conventional X-ray and cisplatin therapies to increase their cytotoxic effect while lowering the effective dose.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Parkin DM (2001) Global cancer statistics in the year 2000. Lancet Oncol 2(9):533–543

    Article  PubMed  CAS  Google Scholar 

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90

    Article  PubMed  Google Scholar 

  3. Steben M, Duarte-Franco E (2007) Human papillomavirus infection: epidemiology and pathophysiology. Gynecol Oncol 107(Suppl 1):S2–S5

    Article  PubMed  CAS  Google Scholar 

  4. DiMaio D, Liao JB (2006) Human papillomaviruses and cervical cancer. Adv Virus Res 66:125–159

    Article  PubMed  CAS  Google Scholar 

  5. Schiller JT, Castellsague X, Villa LL, Hildesheim A (2008) An update of prophylactic human papillomavirus L1 virus-like particle vaccine clinical trial results. Vaccine 26(Suppl 10):K53–K61

    Article  PubMed  CAS  Google Scholar 

  6. Lin K, Doolan K, Hung CF, Wu TC (2010) Perspectives for preventive and therapeutic HPV vaccines. J Formos Med Assoc 109(1):4–24

    Article  PubMed  CAS  Google Scholar 

  7. Movva S, Rodriguez L, Arias-Pulido H, Verschraegen C (2009) Novel chemotherapy approaches for cervical cancer. Cancer 115(14):3166–3180

    Article  PubMed  CAS  Google Scholar 

  8. Serkies K, Jassem J (2005) Chemotherapy in the primary treatment of cervical Carcinoma. Crit Rev Oncol Hematol 54(3):197–208

    Article  PubMed  Google Scholar 

  9. Maduro JH, Pras E, Willemse PH, de Vries EGE (2003) Acute and long-term toxicity following radiotherapy alone or in combination with chemotherapy for locally advanced cervical cancer. Cancer Treat Rev 29(6):471–488

    Article  PubMed  CAS  Google Scholar 

  10. Siddik ZH (2003) Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 22(47):7265–7279

    Article  PubMed  CAS  Google Scholar 

  11. Savarese A, Cognetti F (2003) New Drugs in the treatment of recurrent or metastatic cervical cancer. Crit Rev Oncol Hematol 48(3):323–327

    Article  PubMed  Google Scholar 

  12. Hougardy BM, Maduro JH, Vander Zee AGJ, Willemse PHB, deJong S, de Vries EGE (2005) Clinical potential of inhibitors of survival pathways and activators of apoptotic pathways in treatment of cervical cancer: changing the apoptotic balance. Lancet Oncol 6(8):589–598

    Article  PubMed  CAS  Google Scholar 

  13. Flescher E (2007) Jasmonates in cancer therapy. Cancer Lett 245(1–2):1–10

    Article  PubMed  CAS  Google Scholar 

  14. Cohen S, Flescher E (2009) Methyl jasmonate: a plant stress hormone as an anti-cancer drug. Phytochemistry 70(13–14):1600–1609

    Article  PubMed  CAS  Google Scholar 

  15. Rotem R, Heyfets A, Fingrut O, Blickstein D, Shaklai M, Flescher E (2005) Jasmonates: novel anticancer agents acting directly and selectively on human cancer cell mitochondria. Cancer Res 65(5):1984–1993

    Article  PubMed  CAS  Google Scholar 

  16. Kniazhanski T, Jackman A, Heyfets A, Gonen P, Flescher E, Sherman L (2008) Methyl jasmonate induces cell death with mixed characteristics of apoptosis and necrosis in cervical cancer cells. Cancer Lett 271(1):34–46

    Article  PubMed  CAS  Google Scholar 

  17. Milrot E, Jackman A, Kniazhanski T, Gonen P, Flescher E, Sherman L (2012) Methyl jasmonate reduces the survival of cervical cancer cells and downregulates HPV E6 and E7, and survivin. Cancer Lett 319(1):31–38

    Article  PubMed  CAS  Google Scholar 

  18. Takimoto C, Calvo E (2005) Principles of oncologic pharmacotherapy. In: Pazdur R, Coia LR, Hoskins WJ, Wagman LD (eds) Cancer management: a multidisciplinary approach. CMP Healthcare Media, Manhasset, pp 23–42

    Google Scholar 

  19. Heyfets A, Flescher E (2007) Cooperative cytotoxicity of methyl jasmonate with anti-cancer drugs and 2-deoxy-D-glucose. Cancer Lett 250(2):300–310

    Article  PubMed  CAS  Google Scholar 

  20. Yeruva L, Hall C, Abiodun J, Elegbede JA, Carper SW (2010) Perillyl alcohol and methyl jasmonate sensitize cancer cells to cisplatin. Anticancer Drugs 21(1):1–9

    Article  PubMed  CAS  Google Scholar 

  21. Ezekwudo D, Shashidharamurthy R, Devineni D, Bozeman E, Palaniappan R, Selvaraj P (2008) Inhibition of expression of anti-apoptotic protein Bcl-2 and induction of cell death in radioresistant human prostate adenocarcinoma cell line (PC-3) by methyl jasmonate. Cancer Lett 270(2):277–285

    Article  PubMed  CAS  Google Scholar 

  22. Arazi L, Cooks T, Schmidt M, Keisari Y, Kelson I (2007) Treatment of solid tumors by interstitial release of recoiling short-lived alpha emitters. Phys Med Biol 52(16):5025–5042

    Article  PubMed  CAS  Google Scholar 

  23. Cooks T, Arazi L, Schmidt M, MarshakG KI, Keisari Y (2008) Growth retardation and destruction of experimental squamous cell carcinoma by interstitial radioactive wires releasing diffusing alpha-emitting atoms. Int J Cancer 122(7):1657–1664

    Article  PubMed  CAS  Google Scholar 

  24. Cooks T, Schmidt M, Bittan H, Lazarov E, Arazi L, Kelson I, Keisari Y (2009) Local control of lung derived tumors by diffusing alpha-emitting atoms released from intratumoral wires loaded with radium-224. Int J Radiat Oncol Biol Phys 74(3):966–973

    Article  PubMed  CAS  Google Scholar 

  25. Horev-Drori G, Cooks T, Bittan H, Lazarov E, Scmidt M, Arazi L, Efrati M, Kelson I, Keisari Y (2012) Local control of malignant pancreatic tumors by a combined treatment with intratumoral 225Radium-loaded wires releasing alpha-emitting atoms and chemotherapy. Transl Res 159(1):32–41

    Article  PubMed  CAS  Google Scholar 

  26. Lazarov E, Arazi L, Efrati M, Crooks T, Scmidt M, Keisari Y, Kelson I (2012) Comparative in vitro microdosimetric study of murine-and human-derived cancer cells exposed to alpha particles. Radiat Res 177(3):280–287

    Article  PubMed  CAS  Google Scholar 

  27. Alfandari J, Shnitman Magal S, Jackman A, Schlegel R, Gonen P, Sherman L (1999) HPV16 E6 oncoprotein inhibits apoptosis induced during serum-calcium differentiation of foreskin human keratinocytes. Virology 257(2):383–396

    Article  PubMed  CAS  Google Scholar 

  28. Zhao L, Wientjes MG, Au JL (2004) Evaluation of combination chemotherapy: integration of nonlinear regression, curve shift, isobologram and combination index analyses. Clin Cancer Res 10(23):7994–8004

    Article  PubMed  CAS  Google Scholar 

  29. Cullen KJ, Yang Z, Schumaker L, Guo Z (2007) Mitochondria as a critical target of the chemotherapeutic agent cisplatin in head and neck cancer. J Bioenerg Biomembr 39(1):43–50

    Article  PubMed  CAS  Google Scholar 

  30. Ahamad A, Jhingran A (2004) New radiation techniques in gynecological cancer. Int J Gynecol Cancer 14(4):569–579

    Article  PubMed  CAS  Google Scholar 

  31. Mauceri HJ, Hanna NN, Beckett MA, Gorski DH, Staba MJ, Stellato KA, Bigelow K, Heimann R, Gately S, Dhanabal M, Soff GA, Sukhatme VP, Kufe DW, Weichselbaum RR (1998) Combined effects of angiostatin and ionizing radiation in antitumour therapy. Nature 394(6690):287–291

    Article  PubMed  CAS  Google Scholar 

  32. Katzung BG (1998) Nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, analgesics, and drugs nonopioid used in gout. In: Katzung BG (ed) Basic and clinical pharmacology. Appleton & Lange, Stamford (CT), pp 578–602

    Google Scholar 

  33. Pouget JP, Mather SJ (2001) General aspects of the cellular response to low- and high-LET radiation. Eur J Nucl Med 28(4):541–561

    Article  PubMed  CAS  Google Scholar 

  34. Mori E, Takahashi A, Yamakawa N, Kirita T, Ohnishi T (2009) High LET heavy ion radiation induces p53-independent apoptosis. J Radiat Res 50(1):37–42

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by a research grant from the Chief Scientist’s Office, Ministry of Health, Israel (grant 3–3066) awarded to LS and in part by a grant from the Bernard Jacobson Fund for Cancer Research, Tel-Aviv University, awarded to LS, and a grant from the Israel Cancer Association, awarded to YK.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, 69978, Israel

    Elad Milrot, Anna Jackman, Eliezer Flescher, Pinhas Gonen, Yona Keisari & Levana Sherman

  2. School of Physics and Astronomy, Raymond and Beverly Sackler School of Exact Sciences, Tel-Aviv University, Tel-Aviv, 69978, Israel

    Itzhak Kelson

Authors
  1. Elad Milrot
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anna Jackman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eliezer Flescher
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pinhas Gonen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Itzhak Kelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yona Keisari
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Levana Sherman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Levana Sherman.

Additional information

Dr Eliezer Flescher passed away on 16 May 2011 when this study was in full progress.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Milrot, E., Jackman, A., Flescher, E. et al. Enhanced killing of cervical cancer cells by combinations of methyl jasmonate with cisplatin, X or alpha radiation. Invest New Drugs 31, 333–344 (2013). https://doi.org/10.1007/s10637-012-9870-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-012-9870-2

Keywords

Search

Navigation