Terpinen-4-ol: A Novel and Promising Therapeutic Agent for Human Gastrointestinal Cancers.
BACKGROUND
Terpinen-4-ol, a naturally occurring monoterpene is the main bioactive component of tea-tree oil and has been shown to have many biological activities.


OBJECTIVE
To study the antitumor effects of terpinen-4-ol and its mechanism of action in prostate and GI malignancies, alone and in combination with chemotherapeutic and biological agents.


METHODS
Terpinen-4-ol was administrated alone or combined with standard chemotherapy (Oxaliplatin, Fluorouracil, Gemcitabine, Tarceva) and biological agent (Cetuximab). It was also combined with humanized anti-CD24 mAbs (was developed by us). Killing effects were measured qualitatively by light microscopy and quantitatively using the MTT and FACS analysis, following treatment of colorectal, pancreatic, gastric and prostate cancer cells. Terpinen-4-ol effect on tumor development was evaluated in xenograft model.


RESULTS
Terpinen-4-ol induces a significant growth inhibition of colorectal, pancreatic, prostate and gastric cancer cells in a dose-dependent manner (10-90% in 0.005-0.1%). Terpinen-4-ol and various anti-cancer agents (0.2μM oxaliplatin and 0.5μM fluorouracil) demonstrated a synergistic inhibitory effect (83% and 91%, respectively) on cancer cell proliferation. In KRAS mutated colorectal cancer cells, which are resistant to anti-EGFR therapy, combining of terpinen-4-ol with cetuximab (1 μM) resulted in impressive efficacy of 80-90% growth inhibition. Sub-toxic concentrations of terpinen-4-ol potentiate anti-CD24 mAb (150μg/ml)-induced growth inhibition (90%). Considerable reduction in tumor volume was seen following terpinen-4-ol (0.2%) treatment alone and with cetuximab (10mg/kg) (40% and 63%, respectively) as compare to the control group.


CONCLUSIONS
Terpinen-4-ol significantly enhances the effect of several chemotherapeutic and biological agents. The possible molecular mechanism for its activity involves induction of cell-death rendering this compound as a potential anti-cancer drug alone and in combination in the treatment of numerous malignancies. Terpinen-4-ol restores the activity of cetuximab in cancers with mutated KRAS.
Laboratory of Molecular Biology, The Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel.
Shiran
S
Shapira
EMERALD BIO-LABS LTD, Netanya, Israel.
Shlomo
S
Pleban
Laboratory of Molecular Biology, The Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel.
Diana
D
Kazanov
EMERALD BIO-LABS LTD, Netanya, Israel.
Peter
P
Tirosh
Laboratory of Molecular Biology, The Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel.
Nadir
N
Arber
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D020947:Tea Tree Oil / Q000737:chemistry; D013729:Terpenes / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000972:Antineoplastic Agents, Phytogenic; D009944:Organoplatinum Compounds; D013729:Terpenes; D000077150:Oxaliplatin; D003841:Deoxycytidine; C034019:terpinenol-4; D020947:Tea Tree Oil; D000069347:Erlotinib Hydrochloride; D000068818:Cetuximab; D005472:Fluorouracil; D000093542:Gemcitabine