Common chemotherapeutic regimens in OS include methotrexate, doxorubicin and cisplatin. So far, histological response to neo-adjuvant chemotherapy is the most reliable predictor of survival in non-metastatic OS patients. This disease progression is primarily related to poor chemotherapy response resulting in a very unfavourable prognosis. However 20% of patients without evidence of metastasis at diagnosis either relapse locally or develop systemic disease preferentially by metastasis to the lungs or, less frequently, distant bones. The long-term survival of patients with OS has improved during the last 40 years from 20% to nearly 80% due to the use of neoadjuvant chemotherapy in combination with surgery. Because of a high rate of metastatic spread, curative treatment with surgery alone is rare. Osteosarcoma (OS) is the most common primary malignant bone tumor. Together, our results identify KP46 as a new promising agent to supplement standard chemotherapy and possible future targeted therapy in osteosarcoma. Accordingly, blockade of autophagy by chloroquine but also by the Bcl-2 inhibitor obatoclax increased the cytotoxic activity of KP46 treatment significantly, suggesting autophagy induction as a protective mechanism against KP46. Moreover, the gallium compound induced signs of autophagy in osteosarcoma cells. Furthermore, already at sub-cytotoxic concentrations KP46 reduced the migratory potential of osteosarcoma cells and exerted synergistic effects with cisplatin, a standard osteosarcoma chemotherapeutic. KP46 treatment of osteosarcoma cells caused rapid loss of cell adhesion, weak cell cycle accumulation in S-phase and later signs of apoptotic cell death. KP46 exerted exceptional anticancer activity at the nanomolar to low micromolar range, depending on the assay format, against all osteosarcoma cell models with minor but significant differences in IC 50 values. Underlying mechanisms were tested by cell cycle, apoptosis and autophagy assays. MethodsĪnticancer activity of KP46 against osteosarcoma cell models was evaluated as single agent and in combination approaches with chemotherapeutics and Bcl-2 inhibitors using MTT assay. Hence, development of new therapeutic strategies is still of utmost importance. Although survival has distinctly increased due to neoadjuvant chemotherapy in the past, patients with metastatic disease and poor response to chemotherapy still have an adverse prognosis.
Osteosarcoma is the most frequent primary malignant bone tumor.