ABSTRACT
B cell malignancies are, despite the development of targeted therapy in a certain percentage of the patients still a chronic disease with relapses, requiring multiple lines of therapy. Regimens that include platinum-based drugs provide high response rates in different B cell lymphomas, high-risk chronic lymphocytic leukemia (CLL), and devastating complication of CLL, Richter's syndrome. The aim of this study was to explore the potential antitumor activity of previously synthetized platinum(IV) complex with alkyl derivatives of thyosalicilc acid, PtCl2(S-pr-thiosal)2, toward murine BCL1 cells and to delineate possible mechanisms of action. The PtCl2(S-pr-thiosal)2 reduced the viability of BCL1 cells in vitro but also reduced the growth of metastases in the leukemia lymphoma model in BALB/c mice. PtCl2(S-pr-thiosal)2 induced apoptosis, inhibited proliferation of BCL1 cells, and induced cell cycle disturbance. Treatment of BCL1 cells with PtCl2(S-pr-thiosal)2 inhibited expression of cyclin D3 and cyclin E and enhanced expression of cyclin-dependent kinase inhibitors p16, p21, and p27 resulting in cell cycle arrest in the G1 phase, reduced the percentage of BCL1 cells in the S phase, and decreased expression of Ki-67. PtCl2(S-pr-thiosal)2 treatment reduced expression of phosphorylated STAT3 and downstream-regulated molecules associated with cancer stemness and proliferation, NANOG, cyclin D3, and c-Myc, and expression of phosphorylated NFκB in vitro and in vivo. In conclusion, PtCl2(S-pr-thiosal)2 reduces STAT3 and NFκB phosphorylation resulting in inhibition of BCL1 cell proliferation and the triggering of apoptotic cell death.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Leukemia , Lymphoma, Large B-Cell, Diffuse , Animals , Cell Cycle , Cyclin D3 , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , MiceABSTRACT
Aim: We investigated the antitumor effects of zinc(II) complex with S-propyl thiosalicylic acid [Zn(S-pr-thiosal)2] in 4T1 murine breast cancer model. Results: The Zn(S-pr-thiosal)2 complex reduced primary tumor growth in vivo and induced tumor cell apoptosis. The Zn(S-pr-thiosal)2 complex disrupted the balance between pro- and antiapoptotic Bcl-2 family members in 4T1 cells and induced G1/S cell cycle arrest. The Zn(S-pr-thiosal)2 complex increased the percentage of p16, p21 and p27 positive 4T1 cells. There was a significantly decrease in expression of STAT3 and its targets c-Myc and cyclin D3 in 4T1 cells treated with the Zn(S-pr-thiosal)2 complex thus contributing to G1/S cell cycle arrest and/or apoptosis. Conclusion: Our data suggest that the Zn(S-pr-thiosal)2 complex restricted tumor growth through induction of mitochondrial-driven apoptosis and suppression of cell cycle progression.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Coordination Complexes/pharmacology , Sulfhydryl Compounds/pharmacology , Zinc/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Cycle Checkpoints/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Drug Screening Assays, Antitumor , Female , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred BALB C , Sulfhydryl Compounds/chemistry , Zinc/chemistryABSTRACT
Non-small cell lung cancer is the most common type of lung cancer (about 80% of all lung cancers). It grows and spreads more slowly than small cell lung cancer, but still, when the primary tumour treatment starts, about 60% of patients with cancer already have some kind of malignant cell spreading. Metastases to hand bones and skeletal muscles are very rare (metastatic hand lesions represent 0.1% of all osseous metastases while metastases to muscles represent from 0.8 to 16% incidence in autopsy series); in case of metastases in such sites it can be usually expected to find metastases disseminated all over the body. Fine needle aspiration cytology has an important role to give accurate diagnosis or at least diagnosis of suspicion and thus to set the guidelines to a clinician for the further specific and cost-effective treatment. We will show two cases where the metastases of non-small cell lung carcinoma were the first signs of the disease located in uncommon body parts: a man with the metastasis to distal phalanx of the right thumb and a woman with nodal metastasis to the right gluteal muscle and subcutaneous tissue near muscle which show us that we have to pay our attention to the potential development of such lesions even on rare locations and even when there are no other symptoms. In both cases, patients did not have any other symptoms related to the lung cancer.
