Rhodacyanine Derivative Selectively Targets Cancer Cells and Overcomes Tamoxifen Resistance

John Koren,Yoshinari Miyata,Chad A Dickey,Xiokai Li,Jason E Gestwicki,Laura J Blair,Jianping Guo,Janine Kiray,Jin Q Cheng,Lana Nguyen,Umesh K Jinwal,John C O'Leary

doi:10.1371/journal.pone.0035566

Abstract

MKT-077, a rhodacyanine dye, was shown to produce cancer specific cell death. However, complications prevented the use of this compound beyond clinical trials. Here we describe YM-1, a derivative of MKT-077. We found that YM-1 was more cytotoxic and localized differently than MKT-077. YM-1 demonstrated this cytotoxicity across multiple cancer cell lines. This toxicity was limited to cancer cell lines; immortalized cell models were unaffected. Brief applications of YM-1 were found to be non-toxic. Brief treatment with YM-1 restored tamoxifen sensitivity to a refractory tamoxifen-resistant MCF7 cell model. This effect is potentially due to altered estrogen receptor alpha phosphorylation, an outcome precipitated by selective reductions in Akt levels (Akt/PKB). Thus, modifications to the rhodocyanine scaffold could potentially be made to improve efficacy and pharmacokinetic properties. Moreover, the impact on tamoxifen sensitivity could be a new utility for this compound family.

Highlights

MKT-077, a cationic rhodacyanine, has demonstrated cancer specific toxicity and growth inhibition in vitro and in vivo across multiple cancer varieties [1]
Later it was discovered that MKT-077 interacted with mortalin, a 70-kda heat shock protein (Hsp70) family member, and that the interaction of MKT-077 with mot-2 induced the release of the tumor suppressor p53 from a complex with mot-2 [4]
The derivative YM-1 was the only compound found to have dose dependently higher toxicity than MKT-077 after 24 hours (LDH values normalized for cell number)(Figure 1A)

Summary

Introduction

MKT-077, a cationic rhodacyanine, has demonstrated cancer specific toxicity and growth inhibition in vitro and in vivo across multiple cancer varieties [1]. The observed toxicity halted recruitment to one trial as similar animal studies showed irreversible renal toxicity following administration of MKT-077 [2,3]. Later it was discovered that MKT-077 interacted with mortalin (mot-2), a 70-kda heat shock protein (Hsp70) family member, and that the interaction of MKT-077 with mot-2 induced the release of the tumor suppressor p53 from a complex with mot-2 [4]. This mot-2/p53 complex inactivated the tumor suppression abilities of p53 by sequestering it in the cytosol in vivo [5]

Methods

Results

Conclusion