Abstract
Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor mainly caused by mutations in the RET proto-oncogene. We previously demonstrated that depletion of the mitochondrial molecular chaperone, mortalin, can effectively suppress human MTC cells in culture and in mouse xenografts, by disrupting mitochondrial bioenergetics and subsequently inducing apoptosis and RET downregulation. Similar effects were induced by MKT-077, a water-soluble rhodocyanine dye analog known to inhibit mortalin, but with notable toxicity in animals. These observations led us to evaluate recently developed MKT-077 analogs that exhibited higher selectivity to HSP70 proteins and improved bioavailability. We validated the MTC cell-suppressive effects of mortalin depletion in three-dimensional cultures of the human MTC lines, TT, and MZ-CRC-1, and then evaluated different MKT-077 analogs in two- and three-dimensional cell cultures, to show that the MKT-077 analogs, JG-98 and JG-194, effectively and consistently inhibited propagation of TT and MZ-CRC-1 cells in these cultures. Of note, these compounds also effectively suppressed the viability of TT and MZ-CRC-1 progenies resistant to vandetanib and cabozantinib. Moreover, JG-231, an analog with improved microsomal stability, consistently suppressed TT and MZ-CRC-1 xenografts in mice. These data suggest that mortalin inhibition may have therapeutic potential for MTC.
Highlights
Medullary thyroid carcinoma (MTC) is a relatively rare endocrine tumor that originates from parafollicular C-cells of the thyroid gland, accounting for about 5% of all thyroid cancers [1]
The etiology of MTC is mainly attributed to mutations in the receptor tyrosine kinase, rearranged during transfection (RET), other oncogenic mutations are detected in MTC [2–4]
Consistent with this, similar growth inhibitory effects were induced in MTC cells by MKT-077 (1-ethyl-2-[[3-ethyl-5-(3-methylbenzothiazolin-2yliden)]-4-oxothiazolidin-2-ylidenemethyl] pyridinium chloride), a water-soluble lipophilic cationic rhodocyanine dye, known for its tendency to partition into mitochondria and ability to inhibit a few HSP70 family members, including mortalin and HSC70 [16,17]
Summary
Medullary thyroid carcinoma (MTC) is a relatively rare endocrine tumor that originates from parafollicular C-cells of the thyroid gland, accounting for about 5% of all thyroid cancers [1]. Mitochondrial metabolism is often reprogrammed in cancer in response to the increased demands of tumor cells for energy and building blocks [10] This provides a rationale to target mitochondria for cancer therapy [11,12], which may be applicable for designing a therapeutic strategy for MTC. Consistent with this, similar growth inhibitory effects were induced in MTC cells by MKT-077 (1-ethyl-2-[[3-ethyl-5-(3-methylbenzothiazolin-2yliden)]-4-oxothiazolidin-2-ylidenemethyl] pyridinium chloride), a water-soluble lipophilic cationic rhodocyanine dye, known for its tendency to partition into mitochondria and ability to inhibit a few HSP70 family members, including mortalin and HSC70 [16,17]. These findings suggest that mortalin inhibition is a potential strategy to trigger mitochondrial death in MTC cells. Our data demonstrate that certain benzothiazole rhodacyanine derivatives of MKT-077 can effectively suppress these MTC cells in vitro and in vivo
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