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Table 1.

PA-L1/LF, PA/LF, and PA/FP59 induced proliferation inhibition and cytotoxicity of human melanoma cell lines

Cell linePA-L1/LF ([3H]thymidine, pmol/L)PA/LF IC50 ([3H]thymidine, pmol/L)PA/FP59 IC50 ([3H]thymidine, pmol/L)MAPK pathway mutational statusReference
(A) PA-L1/LF-sensitive melanoma cell lines      
    SK-MEL-24 V600E B-RAF (10) 
    WM793B 11 V600E B-RAF (29) 
    C32 11 V600E B-RAF (10) 
    WM115 19 8.7 0.65 V600E B-RAF (25) 
    WM46 55 12 7.8 V600E B-RAF  
    Malme-3M 64 54 25 V600E B-RAF (10) 
    HT-144 104 25 V600E B-RAF (10) 
    WM983A 109 16 5.1 V600E B-RAF (10) 
    WM-266-4 119 58 V600E B-RAF (10) 
    1205Lu 147 14 V600E B-RAF (29) 
    WM852 159 14 0.7 Q61R NRAS  
    WM51 177 54 15 V600E B-RAF  
(B) PA-L1/LF-resistant, PA/LF-sensitive melanoma cell lines      
    G361 225 44 V600E B-RAF (10) 
    A375 247 93 V600E B-RAF (10) 
    A101D 335 30 V600E B-RAF  
    SK-MEL-28 359 15 V600E B-RAF (10) 
    451Lu 841 57 5.7 V600E B-RAF (30) 
    WM902B 1,010 33 10 V600E B-RAF  
(C) PA/LF-resistant melanoma cell lines      
    SK-MEL-2 407 319 130 Q61K NRAS (10) 
    WM1361A 419 248 4.7 Q61R NRAS (29) 
    SK-MEL-173 757 286 6.4 Wild-type B-RAF  
    A2058 >10,000 >10,000 1.9 Heterozygous V600E B-RAF  
    WM1158 >10,000 >10,000 0.5 V600E B-RAF  
    WM239A >10,000 >10,000 0.4 Wild-type B-RAF  
    WM3211 >10,000 >10,000 Wild-type B-RAF/NRAS  
Cell linePA-L1/LF ([3H]thymidine, pmol/L)PA/LF IC50 ([3H]thymidine, pmol/L)PA/FP59 IC50 ([3H]thymidine, pmol/L)MAPK pathway mutational statusReference
(A) PA-L1/LF-sensitive melanoma cell lines      
    SK-MEL-24 V600E B-RAF (10) 
    WM793B 11 V600E B-RAF (29) 
    C32 11 V600E B-RAF (10) 
    WM115 19 8.7 0.65 V600E B-RAF (25) 
    WM46 55 12 7.8 V600E B-RAF  
    Malme-3M 64 54 25 V600E B-RAF (10) 
    HT-144 104 25 V600E B-RAF (10) 
    WM983A 109 16 5.1 V600E B-RAF (10) 
    WM-266-4 119 58 V600E B-RAF (10) 
    1205Lu 147 14 V600E B-RAF (29) 
    WM852 159 14 0.7 Q61R NRAS  
    WM51 177 54 15 V600E B-RAF  
(B) PA-L1/LF-resistant, PA/LF-sensitive melanoma cell lines      
    G361 225 44 V600E B-RAF (10) 
    A375 247 93 V600E B-RAF (10) 
    A101D 335 30 V600E B-RAF  
    SK-MEL-28 359 15 V600E B-RAF (10) 
    451Lu 841 57 5.7 V600E B-RAF (30) 
    WM902B 1,010 33 10 V600E B-RAF  
(C) PA/LF-resistant melanoma cell lines      
    SK-MEL-2 407 319 130 Q61K NRAS (10) 
    WM1361A 419 248 4.7 Q61R NRAS (29) 
    SK-MEL-173 757 286 6.4 Wild-type B-RAF  
    A2058 >10,000 >10,000 1.9 Heterozygous V600E B-RAF  
    WM1158 >10,000 >10,000 0.5 V600E B-RAF  
    WM239A >10,000 >10,000 0.4 Wild-type B-RAF  
    WM3211 >10,000 >10,000 Wild-type B-RAF/NRAS  

NOTE: PA-L1/LF, PA/LF, and PA/FP59 cytotoxicity to human melanoma cells. Twenty-five melanoma cell lines were tested for PA-L1/LF sensitivity as described in Materials and Methods. Assays were done in triplicate with IC50 variability between assays of <30% and the IC50 values were subsequently tabulated. (A) Twelve cell lines were sensitive to PA-L1/LF as well as PA/LF (IC50 <200 pmol/L with <10% of control [3H]thymidine incorporation at 10 nmol/L PA-L1/1 nmol/L LF), whereas 13 melanomas were resistant to PA-L1/LF. (B) The PA-L1/LF-resistant cell lines G361, A375, A101D, SK-MEL-28, 451Lu, and WM902B were sensitive to PA/LF (IC50 <200 pmol/L with <10% of control [3H]thymidine incorporation at 10 nmol/L PA/1 nmol/L) LF and thus exhibited MAPK dependency. (C) The PA-L1-resistant SK-MEL-2 showed resistance to PA/FP59, which suggested low LeTx receptor expression. The PA/FP59-sensitive WM1361A, SK-MEL-173, A2058, WM1158, WM239A, and WM3211 were not sensitive to PA/LF, which indicated tolerance for LF-mediated MAPK inhibition.

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