實驗的第一部份證實OSU-DY7可以經由活化p38路徑而產生對慢性淋巴球性白血病或Burkitt淋巴瘤的療效。第二個部份證實一個組蛋白去乙醯酶的抑制劑(S)-HDAC42對多發性骨髓瘤的效果。最後我們用一個Akt路徑抑制劑OSU-03012增強imatinib對骨髓瘤細胞的毒殺作用，而此交互作用可能和AMP-活化蛋白激酶與STAT3路徑有關。因此我們的實驗證實，作用於p38 MAPK，Akt路徑或histone deacetylase的藥物可以用來治療淋巴球性血液惡性疾病。當然這方面的研究未來還需要更多實驗來檢視。
Hematological malignancies can be grouped as either myeloid or lymphoid disorders. The standard treatment strategy for lymphoid malignancies is chemotherapeutic agents, usually in combination with monoclonal antibodies which have introduced great impact on the clinical situation. Although certain subtypes of lymphoid malignancies, e.g. diffuse large B cell lymphoma, have good response to initial treatment, some of patients will succumb to the disease because of development of drug resistance. Still others are primarily refractory to initial therapy. The prognosis for these patients is dismal. This highlights the necessity of developing approaches to improve the therapeutic efficacy for lymphoid malignancies. One approach is to develop compounds that have anti-tumor effects with mechanism different from conventional chemotherapeutic agents. Another strategy to improve the therapeutic efficacy is to sensitize cancer cells to cytotoxic effect of other agents. We hypothesize that agents targeting alternative pathways are effective in treatment of lymphoid malignancies. These agents can exhibit anti-tumor efficacy either by themselves or by sensitizing cancer cells to other cytotoxic agents. For this sack, we validate our hypothesis through three approaches.
The first part demonstrates that OSU-DY7 induces cytotoxicity in chronic lymphocytic leukemia and Burkitt lymphoma through activating p38 mitogen-activated protein kinase pathway. The second part illustrates the effectiveness of a histone deacetylase inhibitor (S)-HDAC42 in multiple myeloma cells U266. The last part shows that OSU-03012, an Akt pathway inhibitor, sensitizes myeloma cells to imatinib mesylate via AMP-activated protein kinase and STAT3 pathways. Our study successfully proves the hypothesis that agents targeting p38 MAPK, Akt pathways or histone deacetylase are effective in treatment of lymphoid malignancies. Further studies are needed to shed more light on the road.
