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Radiosensitization by pan ErbB inhibitor CI-1033 in vitro and in vivo
Mukesh K Nyati1, Divya Maheshwari, Sheela Hanasoge
1Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109-0010, USA.
Purpose:
Overexpression of the ErbB family of receptor tyrosine kinases has been associated with uncontrolled growth of many tumor types and, therefore, presents a promising molecular target for cancer therapy. CI-1033 is a small molecule tyrosine kinase inhibitor that differs from other 4-anilinoquinazolines by being a pan ErbB (instead of epidermal growth factor receptor-specific) irreversible (instead of reversible) inhibitor. Therefore, we investigated the antitumor effect of CI-1033 alone and in combination with ionizing radiation in vitro and in vivo.
Experimental Design:
We selected three human colon carcinoma cell-lines (LoVo, Caco-2, which express activated epidermal growth factor receptor and ErbB-2 family members, and SW620, which does not), and analyzed the effects of CI-1033 both in vitro and in vivo. For in vivo studies LoVo and Caco-2 cells were implanted s.c. in the flank of nude mice. After the tumor reached approximately 100 mm(3), treatment was initiated with 20 mg/kg of CI-1033 (orally once daily x 5 for 3 successive weeks), radiation treatment (a total of 30 Gy given in 2 Gy once daily x 5 for 3 successive weeks), or a combination of both CI-1033 and radiation treatment.
Results:
We found that exposure of LoVo and Caco-2, but not SW620 cells, to CI-1033 in the range of 1-3 micro M could inhibit constitutive signaling by tyrosine kinases, arrest cell growth, inhibit cells in G(1), stimulate expression of p53, and induce apoptosis. The inhibition of cell growth by CI-1033 seemed to produce only minimal radiosensitization in LoVo and Caco-2 cells. In contrast, the combination of CI-1033 and radiation produced significant (P < 0.0005 and P = 0.0002, respectively) and prolonged suppression of tumor growth in both the tumor types when compared with either treatment alone.
Conclusions:
These findings suggest that CI-1033 can increase the effectiveness of radiation therapy. The extent of suppression of tyrosine kinase activity by CI-1033, rather than the amount of activity in untreated cells, seemed to be more closely associated with the efficacy of combination treatment.
Insights
The tyrosine kinase inhibitor CI-1033, when combined with radiation, significantly suppressed tumor growth in colon cancer models. This combination therapy enhances the effectiveness of radiation treatment for ErbB-driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- ErbB receptor tyrosine kinases are crucial for tumor growth.
- CI-1033 is a pan-ErbB irreversible tyrosine kinase inhibitor.
- Targeting ErbB signaling is a key strategy in cancer therapy.
Purpose of the Study:
- To investigate the antitumor effects of CI-1033 alone and in combination with ionizing radiation.
- To evaluate CI-1033's efficacy in human colon carcinoma cell lines and in vivo models.
- To determine if CI-1033 potentiates radiation therapy.
Main Methods:
- Utilized three human colon carcinoma cell lines (LoVo, Caco-2, SW620) for in vitro and in vivo studies.
- Administered CI-1033 (20 mg/kg orally) and/or radiation (30 Gy) to nude mice bearing LoVo or Caco-2 tumors.
- Analyzed effects on tyrosine kinase signaling, cell cycle, apoptosis, and tumor growth suppression.
Main Results:
- CI-1033 inhibited tyrosine kinase signaling, arrested cell growth, and induced apoptosis in sensitive cell lines (LoVo, Caco-2).
- CI-1033 showed minimal radiosensitization when used alone.
- Combination therapy with CI-1033 and radiation resulted in significant and prolonged tumor growth suppression.
Conclusions:
- CI-1033 can enhance the efficacy of radiation therapy.
- The degree of tyrosine kinase inhibition by CI-1033 correlates with combination treatment success.
- CI-1033 represents a potential therapeutic agent for improving radiation outcomes in ErbB-related cancers.
