Lipoic acid and lipoic acid analogs in cancer metabolism and chemotherapy

Abstract

The lipoic acid (lipoate) coenzyme is unique in all of mammalian metabolism. It is not only crucial to the function of some of the major enzymes feeding carbon into the tricarboxylic acid cycle, but also generates dynamic regulatory information about the metabolic status of the mitochondrial matrix, ultimately functioning to control these metabolic fluxes. Moreover, these lipoate-sensitive regulatory processes are apparently systematically redesigned in tumor cells and the affected enzymes commonly become especially central to cancer metabolism. Thus, lipoate-sensitive regulatory processes constitute potentially uniquely valuable targets for chemotherapeutic attack. Our goal here is to review the current status of our knowledge relevant to the use of lipoate and lipoate analogs to therapeutically attack malignant disease.

Keywords::

• cancer metabolism
• chemotherapy
• lipoate
• lipoate analogs
• lipoic acid
• lipoic acid analogs
• tumor mitochondria
• two compartment metabolism

Financial & competing interests disclosure

This work was sponsored by Cornerstone Pharmaceuticals. SD Stuart is employed by Cornerstone Pharmaceuticals, Inc. Z Zachar and PM Bingham have financial interests in Cornerstone Pharmaceuticals, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Robust, perdurant chemotherapeutic suppression of most cancers has remained elusive.

• Tumor cells differ from most normal cells in diverse ways, though many of these differences have yet to yield effective therapeutic opportunities.

• The cancer community has come to recognize, over the past decade, that tumor metabolism differs substantially and multifariously from the metabolism of most normal cells.

• Thus, tumor metabolism has emerged as a new therapeutic target environment whose exceptional promise, however, as yet, remains unrealized.

• Lipoic acid (lipoate [LA]) is not merely a catalytic coenzyme but also occupies a unique position in the regulation of metabolism.

• LA-dependent regulatory processes are reconfigured in tumor mitochondria, inviting cancer-specific targeting.

• Exogenously supplied biogenic LA appears to have only limited anticancer potency, likely reflecting its capacity to modulate cellular redox potential.

• In contrast, appropriately designed xenobiotic LA analogs can directly address LA-dependent, tumor-specific regulatory targets, resulting in efficient, selective tumor cell death.

• LA analogs have been subjected to extensive preclinical investigation as chemotherapeutic agents and ongoing Phase II clinical trials to date have produced encouraging anecdotal responses.

Notes