The thiosemicarbazone, DpC, broadly synergizes with multiple anti-cancer therapeutics and demonstrates temperature- and energy-dependent uptake by tumor cells

Mahendiran Dharmasivam; Mahan Gholam Azad; Rizwana Afroz; Vera Richardson; Patric J Jansson; Des R Richardson

doi:10.1016/j.bbagen.2022.130152

The thiosemicarbazone, DpC, broadly synergizes with multiple anti-cancer therapeutics and demonstrates temperature- and energy-dependent uptake by tumor cells

Biochim Biophys Acta Gen Subj. 2022 Aug;1866(8):130152. doi: 10.1016/j.bbagen.2022.130152. Epub 2022 Apr 15.

Authors

Mahendiran Dharmasivam¹, Mahan Gholam Azad¹, Rizwana Afroz², Vera Richardson¹, Patric J Jansson³, Des R Richardson⁴

Affiliations

¹ Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Sydney, New South Wales 2006, Australia; School of Environment and Science, Griffith University Nathan, Brisbane, Queensland 4111, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland 4111, Australia; Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland 4111, Australia.
² School of Environment and Science, Griffith University Nathan, Brisbane, Queensland 4111, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland 4111, Australia; Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland 4111, Australia.
³ Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Sydney, New South Wales 2006, Australia.
⁴ Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Sydney, New South Wales 2006, Australia; School of Environment and Science, Griffith University Nathan, Brisbane, Queensland 4111, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland 4111, Australia; Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland 4111, Australia; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. Electronic address: d.richardson@griffith.edu.au.

PMID: 35436509
DOI: 10.1016/j.bbagen.2022.130152

Abstract

Background: The di-2-pyridylketone thiosemicarbazones, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), demonstrate potent and selective anti-tumor activity. In fact, DpC entered Phase I clinical trials for advanced and resistant tumors.

Methods: This investigation examined the activity of these thiosemicarbazones in five tumor cell-types compared to nine clinically used chemotherapeutics and also in combination with these drugs.

Results: Dp44mT and especially DpC demonstrated potent anti-proliferative activity that was significantly greater than a range of standard anti-cancer therapeutics. As most anti-cancer drugs are given in combination, further studies were performed to examine the synergistic activity of DpC or Dp44mT with these chemotherapeutics. Combination experiments revealed broad synergy between Dp44mT or DpC upon addition of these drugs, with a sequential protocol of treating first with standard chemotherapies followed by incubation with the thiosemicarbazones being optimal. However, combining DpC and Dp44mT resulted in a pronounced antagonistic drug interaction. To dissect the mechanism of this latter effect, custom-prepared ¹⁴C-DpC was implemented and examined for its uptake by cells. The avid uptake of ¹⁴C-DpC by tumor cells observed at 37 °C was suppressed at 4 °C and by the metabolic inhibitor, sodium fluoride, suggesting a temperature- and energy-dependent mechanism. Furthermore, competition studies using an excess of unlabeled Dp44mT or DpC inhibited ¹⁴C-DpC or ¹⁴C-Dp44mT uptake, respectively, suggesting these ligands utilize the same carrier/receptor, antagonizing the internalization of each other.

Conclusions and general significance: These studies demonstrate the potent and broad anti-proliferative activity of Dp44mT and particularly DpC, and are important for establishing optimized combinations with standard chemotherapies.

Keywords: Carrier/receptor; Dp44mT; DpC; Thiosemicarbazones.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / pharmacology
Biological Transport
Cell Line, Tumor
Temperature
Thiosemicarbazones* / pharmacology

Substances

Antineoplastic Agents
Thiosemicarbazones