Pharmacological profiling of novel non-COX-inhibiting indole-pyran analogues of etodolac reveals high solid tumour activity of SDX-308 in vitro.
SDX-308 and SDX-309 are potent indole-pyran analogues of SDX-101 (R-etodolac) which has anti-tumour activity unrelated to cyclooxygenase-2 inhibition. Their cytotoxic activity was further studied herein using a well-characterized human tumour cell-line panel containing ten cell lines, as well as in 58 primary tumour cell samples from a variety of diagnoses. The indole-pyran analogues of SDX-101 were in general considerably more active in both cancer cell lines and primary tumour samples. Low cross-reactivity with standard agents was observed, indicating a unique mechanism of action. No apparent influence on efficacy was observed via classical mechanisms of multidrug-resistance. SDX-101 and SDX-309 showed higher relative activity in haematological compared to solid tumour samples, while SDX-308 had pronounced solid-tumour activity. High SDX-308 cytotoxic efficacy was observed in non-small cell lung cancer, renal cancer and ovarian cancer samples, and also in chronic lymphocytic leukaemia. In conclusion, the indole-pyran analogues showed a favourable pharmacological profile and represent a potentially important new class of drugs for cancer treatment.
Lindhagen
Elin
E
Uppsala University Hospital, 751 85 Uppsala, Sweden.
Rickardson
Linda
L
Elliott
Gary
G
Leoni
Lorenzo
L
Nygren
Peter
P
Larsson
Rolf
R
Aleskog
Anna
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D017308:Etodolac / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans
D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; C518129:SDX 308; C522289:SDX 309; D017308:Etodolac