Drug repurposing for anticancer therapies. A lesson from proton pump inhibitors

ABSTRACT

Introduction: Worldwide, the annual expenditure on anticancer drugs is grossly calculated to be in the order of US$100 billion, and is expected to escalate up to $150 billion by 2020. It is evident that the vast majority of the most recently devised anticancer drugs are unaffordable in economically developing nations, frequently resulting in subpar therapies. In this complex medical and economic scenario, the repurposing of older drugs for anticancer therapies becomes a necessity. The repurposing of antiacid drugs such as the proton pump inhibitors as antitumoral agents and chemosensitizers is probably one of the most recent and promising phenomenon in oncology.

Areas covered: Important research articles and patents focusing on proton pump inhibitors as a potential class of therapeutics, published between the period of 2006–2019, have been covered. This review mainly focuses on the therapeutic applications, as direct anticancer agents as well as modifiers of the tumor microenvironment and modulator of chemoresistance.

Expert opinion: PPIs have significant anticancer applications and are proving to be safe, effective and inexpensive. Here the authors review the current knowledge regarding the influence of PPIs on the efficacy and safety of cancer chemotherapeutics through the regulation of targets other than the H⁺/K⁺-ATPase.

KEYWORDS:

• Acidity
• chemotherapy
• pH
• proton pump inhibitors
• resistance to drugs
• tumors

Article highlights

• All cancers have an acidic microenvironment

• The major cause of chemoresistance is microenvironmental acidity inasmuch as it leads to drug protonation blocking them outside the cancer cells

• One of the major causes of tumor acidification is PROTON PUMPS that pump H+ outside the cells to avoid intracellular acidification

• Proton pump inhibitors while mostly used as anti-acidic drugs, are able to block tumor cell proton pumps.

• Proton pump inhibitors are prodrugs that only at acidic pH are transformed in the active molecule

• This, on one hand, leads to microenvironmental buffering, in turn allowing an increased drug effectiveness; on the other hands killing cancer cells by inhibiting a mechanism that avoids intracellular acidification

• For the above reason, PPI may be well used as chemosensitizers and anti-cancer drugs.

• There is clinical evidence that PPI may be used in both cancer treatment and cancer prevention.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the Italian Ministry of Health.