Marked activity of irinotecan and rapamycin combination toward colon cancer cells in vivo and in vitro is mediated through cooperative modulation of the mammalian target of rapamycin/hypoxia-inducible factor-1alpha axis.
OBJECTIVE
Despite recent progress, colon cancer is often resistant to combination chemotherapy, highlighting the need for development of novel therapeutic approaches. An attractive target is hypoxia-inducible factor-1alpha (HIF-1alpha), a key transcription factor with a pivotal role in tumor cell metabolism. One potential class of therapeutic agents targeting HIF-1alpha are mammalian target of rapamycin inhibitors such as rapamycin. A second class are topoisomerase I inhibitors, such as irinotecan, which are able to inhibit the accumulation of HIF-1alpha. We here investigated whether combination of rapamycin and irinotecan was active in human colon cancer models.


METHODS
Human metastatic tumors were xenografted in nude mice and treated with low doses of irinotecan alone, rapamycin alone, or combination of both drugs. The cellular effects of irinotecan and rapamycin were further characterized for HT-29 and HCT-116 colon cancer cells in vitro.


RESULTS
In contrast to single-agent therapy, xenografted tumors treated with combination of irinotecan and rapamycin showed potent inhibition of the mammalian target of rapamycin/HIF-1alpha axis, which was accompanied by a dramatic reduction in tumor volume. In vitro experiments showed that exposure to low concentrations of the two drugs resulted in massive HT-29 cell death under hypoxic, but not normoxic, conditions, in full agreement with a cytotoxic effect mediated through HIF-1alpha rather than through induction of genotoxic lesions. HCT-116 cells were less sensitive to the combined treatment due to constitutive activation of phosphatidylinositol 3-kinase/Akt and Ras/mitogen-activated protein kinase pathways.


CONCLUSIONS
These results identify HIF-1alpha as a promising target and provide a rationale for clinical trials of low-dose irinotecan and rapamycin combination toward metastatic colon cancer.
Pencreach
Erwan
E
Institut National de la Santé et de la Recherche Médicale U682, Service de Biochimie et Biologie Moléculaire, Hôpital de Hautepierre Hôpitaux Universitaires de Strasbourg, Strasbourg, France. erwan.pencreach@chru-strasbourg.fr
Guérin
Eric
E
Nicolet
Céline
C
Lelong-Rebel
Isabelle
I
Voegeli
Anne-Claire
AC
Oudet
Pierre
P
Larsen
Annette K
AK
Gaub
Marie-Pierre
MP
Guenot
Dominique
D
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D000077146:Irinotecan; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D020123:Sirolimus / Q000008:administration & dosage* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D002166:Camptothecin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000077146:Irinotecan; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; C497442:HIF1A protein, human; C546842:MTOR protein, human; C546843:mTOR protein, mouse