Preclinical Investigations of PM01183 (Lurbinectedin) as a Single Agent or in Combination with Other Anticancer Agents for Clear Cell Carcinoma of the Ovary

PLoS One. 2016 Mar 17;11(3):e0151050. doi: 10.1371/journal.pone.0151050. eCollection 2016.


Objective: The objective of this study was to evaluate the antitumor effects of lurbinectedin as a single agent or in combination with existing anticancer agents for clear cell carcinoma (CCC) of the ovary, which is regarded as an aggressive, chemoresistant, histological subtype.

Methods: Using human ovarian CCC cell lines, the antitumor effects of lurbinectedin, SN-38, doxorubicin, cisplatin, and paclitaxel as single agents were assessed using the MTS assay. Then, the antitumor effects of combination therapies involving lurbinectedin and 1 of the other 4 agents were evaluated using isobologram analysis to examine whether these combinations displayed synergistic effects. The antitumor activity of each treatment was also examined using cisplatin-resistant and paclitaxel-resistant CCC sublines. Finally, we determined the effects of mTORC1 inhibition on the antitumor activity of lurbinectedin-based chemotherapy.

Results: Lurbinectedin exhibited significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. An examination of mouse CCC cell xenografts revealed that lurbinectedin significantly inhibits tumor growth. Among the tested combinations, lurbinectedin plus SN-38 resulted in a significant synergistic effect. This combination also had strong synergistic effects on both the cisplatin-resistant and paclitaxel-resistant CCC cell lines. Everolimus significantly enhanced the antitumor activity of lurbinectedin-based chemotherapies.

Conclusions: Lurbinectedin, a new agent that targets active transcription, exhibits antitumor activity in CCC when used as a single agent and has synergistic antitumor effects when combined with irinotecan. Our results indicate that lurbinectedin is a promising agent for treating ovarian CCC, both as a first-line treatment and as a salvage treatment for recurrent lesions that develop after platinum-based or paclitaxel treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma, Clear Cell / drug therapy*
  • Adenocarcinoma, Clear Cell / pathology
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Carbolines / administration & dosage
  • Carbolines / therapeutic use*
  • Cell Line, Tumor
  • Cisplatin / administration & dosage
  • Cisplatin / therapeutic use
  • Doxorubicin / administration & dosage
  • Doxorubicin / therapeutic use
  • Drug Synergism
  • Female
  • Heterocyclic Compounds, 4 or More Rings / administration & dosage
  • Heterocyclic Compounds, 4 or More Rings / therapeutic use*
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Nude
  • Multiprotein Complexes / antagonists & inhibitors
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / pathology
  • Ovary / drug effects*
  • Ovary / pathology
  • Paclitaxel / administration & dosage
  • Paclitaxel / therapeutic use
  • TOR Serine-Threonine Kinases / antagonists & inhibitors


  • Antineoplastic Agents
  • Carbolines
  • Heterocyclic Compounds, 4 or More Rings
  • Multiprotein Complexes
  • PM 01183
  • Doxorubicin
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Paclitaxel
  • Cisplatin

Grant support

This study was supported by Grant-in-aid for General Scientific Research no. 23592446 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.