Commentary: Novel Therapies for Cancer: Why Dirty Might Be Better

Abstract

In the era of targeted therapy, many have argued that targeted therapies would not only be more effective but also less toxic. However, the early evidence suggests that the assumption that greater specificity would result in greater efficacy may have been premature. In fact, it can be argued that dirty may be better than clean.

Redox-Directed Cancer Therapeutics: Molecular Mechanisms and Opportunities

“…Pharmacological agents that modulate cellular redox homeostasis through direct or indirect alteration of ROS generation, signaling, and turnover are generally considered 'dirty' drugs, a term that refers to pharmacological agents that modulate multiple molecular targets through pleiotropic interactions (111). In the age of molecularly targeted therapy, development of dirty drugs is generally pursued with reduced enthusiasm due to the tendency of these promiscuous agents to produce toxic off-target effects.…”

“…Covalent adduction and generation of reactive intermediates (282) is associated with numerous reactive pharmacophore contained in redox chemotherapeutics (e.g., bisfunctional Michael acceptors, discussed in Section II.G). However, recent research suggests that it is exactly this pleiotropic mode of action associated with numerous redox chemotherapeutics (i.e., the simultaneous modulation of multiple redox sensitive targets) that seems to be uniquely tailored to overcome cancer cell drug resistance originating from redundancy of oncogenic signaling and rapid mutation, as discussed extensively throughout this review (50,111,199). Moreover, lead optimization of prototype redox chemotherapeutics has led to the development of advanced preclinical candidates with pharmacophores that display attenuated and more targeted redox reactivity such as quinones that target Cdc25 phosphatases with attenuated or absent redox cycler activity (discussed in Section III.F) (124).…”

Hope and Fear for Interferon: The Receptor-Centric Outlook on the Future of Interferon Therapy

“…Intrinsic to molecularly targeted therapeutics is the rapid development of resistance due to target-specific or pathway-specific acquired mutations (Barouch-Bentov and Sauer 2011;Watzka and others 2011). This has prompted modern oncopharmacology to revisit its strategy and seek a greater potency at the expense of specificity [reviewed in Fojo (2008)]. Among agents that can combat cancer growth and progression through pleiotropic mechanisms are antitumorigenic cytokines, the interferons (IFNs).…”

Inhibition of Glutathione Peroxidase Mediates the Collateral Sensitivity of Multidrug-resistant Cells to Tiopronin

“…Cellular alterations acquired during the development of multidrug resistance (MDR) 2 include expression of the ATP-binding cassette family of efflux transporters including ABCB1 (also termed P-glycoprotein (P-gp)) and a range of alterations that arise as a result of adaptation to individual drugs in pathways involved in DNA repair, death signaling, drug detoxification, lysosomal changes, and acquisition of point mutations in drug targets (2). Given this broad range of alterations, there is an unmet need for therapeutic strategies that are active against drug-resistant malignancies (3).…”