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Targeting Burkitt lymphoma with a tumor cell–specific heptamethine carbocyanine‐cisplatin conjugate
Author(s) -
Mrdenovic Stefan,
Zhang Yi,
Wang Ruoxiang,
Yin Lijuan,
Chu Gina ChiaYi,
Yin Liyuan,
Lewis Michael,
Heffer Marija,
Zhau Haiyen E.,
Chung Leland W. K.
Publication year - 2019
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.32033
Subject(s) - cancer research , lymphoma , cytotoxic t cell , cell culture , cisplatin , medicine , apoptosis , chemotherapy , biology , pathology , in vitro , biochemistry , genetics
Background Burkitt lymphoma is a fast‐growing mature B cell malignancy, whose genetic hallmark is translocation and activation of the c‐myc gene. Prompt multiagent immunochemotherapy regimens can have favorable outcomes, but prognosis is poor in refractory or relapsed disease. We previously identified a novel family of near‐infrared heptamethine carbocyanine fluorescent dyes (HMCD or DZ) with tumor‐homing properties via organic anion‐transporting peptides. These membrane carriers have uptake in tumor cells but not normal cells in cell culture, mouse and dog tumor models, patient‐derived xenografts, and perfused kidney cancers in human patients. Methods Here we report the cytotoxic effects of a synthesized conjugate of DZ with cisplatin (CIS) on B cell lymphoma CA46, Daudi, Namalwa, Raji, and Ramos cell lines in cell culture and in xenograft tumor formation. Impaired mitochondrial membrane permeability was examined as the mechanism of DZ‐CIS–induced lymphoma cell death. Results The new conjugate, DZ‐CIS, is cytotoxic against Burkitt lymphoma cell lines and tumor models. DZ‐CIS retains tumor‐homing properties to mitochondrial and lysosomal compartments, does not accumulate in normal cells and tissues, and has no nephrotoxicity in mice. DZ‐CIS accumulated in Burkitt lymphoma cells and tumors induces apoptosis and retards tumor cell growth in culture and xenograft tumor growth in mice. Conclusion DZ‐CIS downregulated c‐myc and overcame CIS resistance in myc ‐driven TP53‐mutated aggressive B cell Burkitt lymphoma. We propose that DZ‐CIS could be used to treat relapsed/refractory aggressive Burkitt lymphomas.