Activation of PDGFr-β Signaling Pathway after Imatinib and Radioimmunotherapy Treatment in Experimental Pancreatic Cancer

Pancreatic cancer does not respond to a single-agent imatinib therapy. Consequently, multimodality treatments are contemplated. Published data indicate that in colorectal cancer, imatinib and radioimmunotherapy synergize to delay tumor growth. In pancreatic cancer, the tumor response is additive. This disparity of outcomes merited further studies because interactions between these modalities depend on the imatinib-induced reduction of the tumor interstitial fluid pressure. The examination of human and murine PDGFr-β/PDGF-B pathways in SW1990 pancreatic cancer xenografts revealed that the human branch is practically dormant in untreated tumors but the insult on the stromal component produces massive responses of human cancer cells. Inhibition of the stromal PDGFr-β with imatinib activates human PDGFr-β/PDGF-B signaling loop, silent in untreated xenografts, via an apparent paracrine rescue pathway. Responses are treatment- and time-dependent. Soon after treatment, levels of human PDGFr-β, compared to untreated tumors, are 3.4×, 12.4×, and 5.7× higher in imatinib-, radioimmunotherapy + imatinib-, and radioimmunotherapy-treated tumors, respectively. A continuous 14-day irradiation of imatinib-treated xenografts reduces levels of PDGFr-β and phosphorylated PDGFr-β by 5.3× and 4×, compared to earlier times. Human PDGF-B is upregulated suggesting that the survival signaling via the autocrine pathway is also triggered after stromal injury. These findings indicate that therapies targeting pancreatic cancer stromal components may have unintended mitogenic effects and that these effects can be reversed when imatinib is used in conjunction with radioimmunotherapy

Radiolabeled Cyclosaligenyl Monophosphates of 5-Iodo-2′-deoxyuridine, 5-Iodo-3′-fluoro-2′,3′-dideoxyuridine, and 3′-Fluorothymidine for Molecular Radiotherapy of Cancer: Synthesis and Biological Evaluation

Targeted molecular radiotherapy opens unprecedented opportunities to eradicate cancer cells with minimal irradiation of normal tissues. Described in this study are radioactive cyclosaligenyl monophosphates designed to deliver lethal doses of radiation to cancer cells. These compounds can be radiolabeled with SPECT- and PET-compatible radionuclides as well as radionuclides suitable for Auger electron therapies. This characteristic provides an avenue for the personalized and comprehensive treatment strategy that comprises diagnostic imaging to identify sites of disease, followed by the targeted molecular radiotherapy based on the imaging results. The developed radiosynthetic methods produce no-carrier-added products with high radiochemical yield and purity. The interaction of these compounds with their target, butyrylcholinesterase, depends on the stereochemistry around the P atom. IC₅₀ values are in the nanomolar range. In vitro studies indicate that radiation doses delivered to the cell nucleus are sufficient to kill cells of several difficult to treat malignancies including glioblastoma and ovarian and colorectal cancers

Benzimidazole carbamate induces cytotoxicity in breast cancer cells via two distinct cell death mechanisms

Abstract Metastatic breast cancer (mBC) is responsible for >90% of breast cancer-related deaths. Microtubule-targeting agents (MTAs) are the front-line treatment for mBC. However, the effectiveness of MTAs is frequently limited by the primary or acquired resistance. Furthermore, recurrent mBC derived from cancer cells that survived MTA treatment are typically more chemoresistant. The overall response rates for the second- and third-line MTAs in mBC patients previously treated with MTAs are 12–35%. Thus, there is an ongoing search for novel MTAs with a distinct mode of action that can circumvent chemoresistance mechanisms. Our results show that methyl N-(6-benzoyl-1H- b enzimidazol-2-yl) car bamate (BCar), a microtubule-disrupting anthelmintic that binds to the colchicine binding site separate from the binding sites of clinically used MTAs, has the potential to treat MTA-resistant mBC. We have comprehensively evaluated the cellular effects of BCar in a panel of human breast cancer (BC) cell lines and normal breast cells. BCar effects on the clonogenic survival, cell cycle, apoptosis, autophagy, senescence, and mitotic catastrophe were measured. Approximately 25% of BCs harbor mutant p53. For this reason, the p53 status was included as a variable. The results show that BC cells are >10x more sensitive to BCar than normal mammary epithelial cells (HME). p53-mutant BC cells are significantly more sensitive to BCar treatment than p53 wild-type BC cells. Furthermore, BCar appears to kill BC cells primarily via either p53-dependent apoptosis or p53-independent mitotic catastrophe. When compared to docetaxel and vincristine, two clinical MTAs, BCar is fairly innocuous in HME cells, providing a much wider therapeutic window than docetaxel and vincristine. Together, the results strongly support the notion that BCar-based therapeutics may serve as a new line of MTAs for mBC treatment