Synthetic galectin-3 inhibitor increases metastatic cancer cell sensitivity to taxol-induced apoptosis in vitro and in vivo.
At present, there is no efficient curative therapy for cancer patients with advanced metastatic disease. Targeting of antiapoptotic molecules acting on the mitochondrial apoptosis pathway could potentially augment antimetastatic effect of cytotoxic drugs. Similarly to Bcl-2 family members, beta-galactoside-binding lectin galectin-3 protects cancer cells from apoptosis induced by cytotoxic drugs through the mitochondrial pathway. In this study, we tested the hypothesis that inhibiting galectin-3 antiapoptotic function using a synthetic low-molecular weight carbohydrate-based compound lactulosyl-L-leucine (Lac-L-Leu) will augment apoptosis induced in human cancer cells by paclitaxel and increase its efficacy against established metastases. Treatment with synthetic glycoamine Lac-L-Leu alone reduced the number of established MDA-MB-435Lung2 pulmonary metastases 5.5-fold (P = .032) but did not significantly affect the incidence of metastasis. Treatment with paclitaxel alone (10 mg/kg three times with 3-day intervals) had no significant effect on the incidence or on the number of MDA-MB-435Lung2 metastases. Treatment with Lac-L-Leu/paclitaxel combination decreased both the number (P = .02) and the incidence (P = .001) of pulmonary metastases, causing a five-fold increase in the number of metastasis-free animals from 14% in the control group to 70% in the combination therapy group. The median number of lung metastases dropped to 0 in the combination therapy group compared with 11 in the control (P = .02). Synergistic inhibition of clonogenic survival and induction of apoptosis in metastatic cells by Lac-L-Leu/paclitaxel combination was functionally linked with an increase in mitochondrial damage and was sufficient for the antimetastatic activity that caused a reversal and eradication of advanced metastatic disease in 56% of experimental animals.
Glinsky
Vladislav V
VV
Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA. glinskiivl@missouri.edu
Kiriakova
Galina
G
Glinskii
Olga V
OV
Mossine
Valeri V
VV
Mawhinney
Thomas P
TP
Turk
James R
JR
Glinskii
Anna B
AB
Huxley
Virginia H
VH
Price
Janet E
JE
Glinsky
Gennadi V
GV
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D004338:Drug Combinations; D005697:Galactosides / Q000494:pharmacology*; D037502:Galectin 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007930:Leucine / Q000737:chemistry; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000972:Antineoplastic Agents, Phytogenic; D004338:Drug Combinations; D005697:Galactosides; D037502:Galectin 3; D019253:Proto-Oncogene Proteins c-bcl-2; C007816:beta-galactoside; D007930:Leucine; D017239:Paclitaxel