Table 1.
Examples of U251 human tumor cell genes that constitute beneficial responses (A) or undesirable responses (B) to metronomic CPA treatment
| A. Beneficial responses | ||||||
|---|---|---|---|---|---|---|
| Gene | U251 (day 12) | U251 (day 18) | Pro-tumor or Anti-tumor Activities | References | ||
| Fold change | p-value | Fold change | p-value | |||
| LUM | 8.7 | 1.3E-06 | 14.1 | 1.7E-14 | Inhibits tumor cell migration and invasion | [112] |
| SSTR2 | 5.5 | 7.5E-23 | 5.9 | 0 | Inhibits glioma proliferation | [113] |
| IFNB1 | 5.5 | 9.3E-37 | 5.9 | 2.5E-43 | Pro-apoptotic, anti-proliferative, anti-angiogenic factor; inhibits accumulation of pro-angiogenic tumor-associated neutrophils | [114,115] |
| ZBP1 | 4.8 | 0 | 5.6 | 0 | DNA sensor; activates IRFs, NFkB, and innate immunity; interferon-inducible | [116-118] |
| XAF1 | 2.8 | 2.2E-35 | 5.5 | 0 | Interferon-inducible, pro-apoptotic | [119] |
| IFIT3 | 4.0 | 1.7E-37 | 5.3 | 7.8E-42 | Interferon-inducible, pro-apoptotic | [120] |
| DMBT1 | 3.3 | 7.0E-15 | 5.0 | 0 | Tumor suppressor down-regulated in glioblastoma | [121] |
| DDX58 | 2.8 | 6.5E-43 | 4.5 | 0 | Induces interferon-I, activates apoptosis | [122] |
| TNFSF4/OX40L | 2.3 | 2.5E-08 | 3.5 | 2.8E-31 | Increases adhesion of activated T cells at tumor site | [123] |
| CXCL2/MIP2 | −4.6 | 3.8E-14 | −3.1 | 1.3E-09 | Up-regulated in temozolomide-resistant glioma | [124] |
| CXCR4 | −3.6 | 7.4E-38 | −5.0 | 2.0E-26 | Promotes angiogenesis in glioma | [125,126] |
| LGR5 | −4.7 | 3.8E-43 | −5.3 | 1.2E-39 | Marker for poor prognosis in glioblastoma | [127] |
| IL8/CXCL8 | −7.6 | 1.5E-11 | −5.5 | 1.1E-24 | Proinflammatory cytokine; increases tumor angiogenesis, invasion and metastasis; interferon-inducible | [128] |
| B.B. Undesirable responses | ||||||
| Gene | U251 (day 12) | U251 (day 18) | Pro-tumor or Anti-tumor Activities | References | ||
| Fold change | p-value | Fold change | p-value | |||
| MMP13 | 10.1 | 1.1E-11 | 15.4 | 0 | Promotes tumor cell proliferation and invasion | [129] |
| CEACAM1 | 5.9 | 4.7E-29 | 13.2 | 7.7E-29 | Immune-inhibitory adhesion molecule; interferon-inducible | [94] |
| LAMP3/CD208 | 6.4 | 1.5E-30 | 9.6 | 0 | Promotes metastases | [130] |
| EREG | 6.5 | 2.3E-25 | 8.5 | 0 | Binds EGFR and induces glioma cell growth | [95] |
| IDO1 | 4.8 | 0 | 6.5 | 0 | Immunosuppressive in human glioblastoma; interferon-inducible | [96] |
| ACP5 | 4.5 | 2.3E-33 | 5.0 | 7.2E-39 | Pro-metastatic factor | [131] |
Shown are fold-change values (fold increases or decreases in expression compared to drug-free controls) and associated p-values derived from microarray analyses for U251 tumors analyzed on day 12 and day 18 after initial CPA treatment.