Development of a dichloroacetic acid‐hemoglobin conjugate as a potential targeted anti‐cancer therapeutic

Abstract

This work focuses on conjugating the anti-cancer drug dichloroacetic acid (DCA) to the monocyte/macrophage targeting protein hemoglobin (Hb). The DCA-Hb conjugate carries approximately 12 DCA molecules per Hb tetramer, and binds to haptoglobin (Hp) forming stable DCA-Hb-Hp complexes, in a similar manner to unmodified Hb. The results of this study show that DCA-Hb-Hp is taken up by the monocytic cancer cell line THP-1, where it depolarizes the mitochondrial membrane potential, thereby inhibiting cancerous cell growth at a comparable level to free DCA. Taken together, the results of this study show promise for the use of the DCA-Hb conjugate as a potential therapeutic to treat monocytic leukemia.

AML cells have low spare reserve capacity in their respiratory chain that renders them susceptible to oxidative metabolic stress

“…Through its ability to increase mitochondrial mass and b-oxidation, 30,31 the PPARa agonist bezafibrate may include antileukemic activity. Alternatively, promoting OXPHOS flux with compounds such as 2-deoxyglucose, 3-bromopyruvate, 32,33 or dichloroacetic acid 34 may also selectively induce death in a subset of AML cells, and it could be evaluated alone or in combination with standard chemotherapeutic agents.…”

Restoration of mitochondria function as a target for cancer therapy

“…Of interest, multiple analogs have been synthesized and have shown slightly better efficacy compared with parent DCA. These analogs have been mostly synthesized as a complex of multiple DCA molecules with or without the inclusion of anticancer agents [80, 119–121]. Interesting, a recently developed DCA analog, Mito-DCA, specifically accumulates at mitochondria and has shown higher potency against prostate cancer cells at a micromolar concentration [21].…”

Protein– and Peptide–Drug Conjugates

“…Increased iron requirement in tumor tissues causes 10Â higher expression of TfR in cancer cells as compared to normal cells (Inoue, Cavanaugh, Steck, Brunner, & Nicolson, 1993). Various cancers showing higher expression of TfR include breast cancer, leukemia, colon cancer, skin cancer, glioblasoma, and Hatano et al (1993) and Takahashi, Asakura, and Ohkawa (1996) Doxorubicin • Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln and Gly-Pro-Gln-Arg-Ile-Ala-Gly-Gln linkers showed MMP-2-and MMP-9-specific cleavage in cancer cells • Ile-Ala-Gly-Gln-doxorubicin liberated after cleavage is less active than free drug (IC 50 of conjugates with two linkers is >20 Â and > 300 Â higher than free drug, respectively) Hoshino et al (1995aHoshino et al ( , 1995b Continued Insulin Mitoxantrone • Higher blood residence time, higher tumor targeting and low distribution in normal tissue cells in hepatoma bearing mice Liu, Huang, and Zhang (2003) 5-Fluorouracil • Dendritic linker was used to attach several drug molecules to insulin • Stable in acidic media while drug release at alkaline pH and in presence of plasma ensuring controlled release of drug in blood Huang, Wang, Gong, and Zhang (2007) Hemoglobin Ribavirin • 12 DCA molecules per hemoglobin tetramer • Haptoglobin receptor-mediated uptake by monocytic cancer cells • Activity retained as that of free DCA Zhang and Palmer (2011) lymphoma (Calzolari et al, 2007). Apart from cancer, use of transferrin has also been exploited for oral delivery of drugs (Lim & Shen, 2005;Xia et al, 2000) due to expression of TfRs in GI tract.…”