title: Antitumor activity of paclitaxel is significantly enhanced by a novel proapoptotic agent in non-small cell lung cancer.
abstract: BACKGROUND
  Newer targeted agents are increasingly used in combination chemotherapy regimens with enhanced survival and improved toxicity profile. Taxols, such as paclitaxel, independently potentiate tumor destruction via apoptosis and are used as first line therapy in patients with advanced non-small cell lung cancer (NSCLC). Procaspase-3-activating compound-1 (PAC-1) is a novel proapoptotic agent that directly activates procaspase-3 (PC-3) to caspase-3, leading to apoptosis in human lung adenocarcinoma cells. Hence, we sought to evaluate the antitumor effects of paclitaxel in combination with PAC-1.
  
  
  METHODS
  Human NSCLC cell lines (A-549 and H-322m) were incubated in the presence of PAC-1 and paclitaxel. Tumor cell viability was determined by a tetrazolium-based colorimetric assay (MTT assay). Western blot and flow cytometric analysis were performed to evaluate expression of PC-3 and the proportion of apoptotic cells, respectively. A xenograft murine model of NSCLC was used to study the in vivo antitumor effects of PAC-1.
  
  
  RESULTS
  PAC-1 significantly reduced the inhibitory concentration 50% of paclitaxel from 35.3 to 0.33 nM in A-549 and 8.2 to 1.16 nM in H-322m cell lines. Similarly, the apoptotic activity significantly increased to 85.38% and 70.36% in A-549 and H322m, respectively. Significantly enhanced conversion of PC-3 to caspase-3 was observed with PAC-1 paclitaxel combination (P < 0.05). Mice treated with a drug combination demonstrated 60% reduced tumor growth rate compared with those of controls (P < 0.05).
  
  
  CONCLUSIONS
  PAC-1 significantly enhances the antitumor activity of paclitaxel against NSCLC. The activation of PC-3 and thus the apoptotic pathway is a potential strategy in the treatment of human lung cancer.
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Mount Sinai St. Luke's Hospital, Mount Sinai Health System, New York, NY, USA; Division of Thoracic Surgery, Department of Surgery, Mount Sinai Roosevelt Hospital, Mount Sinai Health System, New York, NY, USA.
authors.forename: Syed S
authors.initials: SS
authors.lastname: Razi
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Mount Sinai St. Luke's Hospital, Mount Sinai Health System, New York, NY, USA; Division of Thoracic Surgery, Department of Surgery, Mount Sinai Roosevelt Hospital, Mount Sinai Health System, New York, NY, USA.
authors.forename: Sadiq
authors.initials: S
authors.lastname: Rehmani
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Mount Sinai St. Luke's Hospital, Mount Sinai Health System, New York, NY, USA; Division of Thoracic Surgery, Department of Surgery, Mount Sinai Roosevelt Hospital, Mount Sinai Health System, New York, NY, USA.
authors.forename: Xiaogui
authors.initials: X
authors.lastname: Li
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Mount Sinai St. Luke's Hospital, Mount Sinai Health System, New York, NY, USA; Division of Thoracic Surgery, Department of Surgery, Mount Sinai Roosevelt Hospital, Mount Sinai Health System, New York, NY, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Park
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Mount Sinai St. Luke's Hospital, Mount Sinai Health System, New York, NY, USA; Division of Thoracic Surgery, Department of Surgery, Mount Sinai Roosevelt Hospital, Mount Sinai Health System, New York, NY, USA.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Schwartz
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Mount Sinai St. Luke's Hospital, Mount Sinai Health System, New York, NY, USA; Division of Thoracic Surgery, Department of Surgery, Mount Sinai Roosevelt Hospital, Mount Sinai Health System, New York, NY, USA.
authors.forename: Mohammed J
authors.initials: MJ
authors.lastname: Latif
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Mount Sinai St. Luke's Hospital, Mount Sinai Health System, New York, NY, USA; Division of Thoracic Surgery, Department of Surgery, Mount Sinai Roosevelt Hospital, Mount Sinai Health System, New York, NY, USA. Electronic address: fybhora@chpnet.org.
authors.forename: Faiz Y
authors.initials: FY
authors.lastname: Bhora
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: C514579:(4-benzylpiperazin-1-yl)acetic acid (3-allyl-2-hydroxybenzylidene)hydrazine; D000970:Antineoplastic Agents; D006835:Hydrazones; D010879:Piperazines; D053148:Caspase 3; D017239:Paclitaxel
keywords: Non–small cell lung cancer; Paclitaxel; Procaspase-3 activating compound-1