Chemosensitizers for Cancer Chemotherapy

Dear Colleagues,

The development of resistance is a major obstacle in cancer therapy since the very early days of chemotherapy in the first half of the 20^th century and even nowadays in times of targeted therapy and precision medicine. Drug resistance may develop during repeated treatment cycles after initially successful therapy (acquired or secondary resistance). Alternatively, tumors may be resistant from the beginning (inherent or primary resistance). The failure of chemotherapy is a major reason for the fatal outcome of tumor diseases in many patients.

The principle of clinically established combination therapy protocols is to prevent resistance to single drugs by hitting the tumor using cocktails of several drugs that act at different targets. Although combination therapy protocols have tremendously improved the survival rates of cancer patients during the past decades, it is unlikely that this strategy is sufficient to reach long-lasting cures of all cancer patients.

The reason for this disappointing situation is that tumors frequently develop not only resistance to single drugs, but also to many others at the same time. This phenomenon is very heterogeneous in its underlying mechanisms and decreases the success rates of therapy regimens with combinations of structurally and functionally different drugs. The term multidrug resistance, with drug efflux by ABC transporters as the underlying mechanism, has been coined to describe one mechanism of resistance of tumor cells to a broad spectrum of drugs. It turned out, however, that the reality in cancer patients is much more complex and a multitude of other mechanisms also have to be taken into account to explain why patients still die from their tumor.

Another strategy to overcome multifactorial drug resistance by combination therapies is the use of chemosensitizers that inhibit specific mechanisms of drug resistance, ultimately leading to a resensitization of tumors towards standard anticancer drugs. Owing to the multi-facetted nature of resistance, chemosensitizers inhibiting single drug resistance mechanisms are unlikely to sufficiently improve the success of conventional chemotherapy. Therefore, a more composing view on tumors is necessary not only to explore the full diversity of drug resistance mechanisms, but also to identify novel therapeutic interventions targeting the critical Achilles’ heel of tumors.

The intention of the planned book is to give an overview of the latest developments from basic pharmacological research on chemosensitizers for cancer therapy. To apply a systematic approach, we should recall that all pharmacological processes in the human body are determined by pharmacokinetic and pharmacodynamic factors. Pharmacokinetics describes the fate of a drug from uptake into the human body until its elimination, whereas pharmacodynamics investigates how drugs exert physiological, biochemical and molecular biological effects of drugs on the body. Anticancer drugs can be subject to the development of resistance at the various pharmacokinetic and pharmacodynamic mechanisms. In the planned book, the most exciting topics will be covered:

Pharmacokinetic factors include the liberation of a drug and the subsequent absorption (entering the blood circulation), distribution (dispensation of a drug throughout the body), metabolization (chemical transformation of a drug into active or inactive metabolites) and excretion (removal of a drug) (ADME) in the body.

• Novel pharmaceutical formulations determine drug liberation into the body. Nanotechnology represents a thriving new field of research in the past few years and numerous nanotechnological devices have been developed that are able to overcome drug resistance in vitro and in vivo.
• ADME of anticancer drugs is mainly driven by the activity phase I enzymes (e.g., oxidation by cytochrome P450 monooxygenases or drug reduction and hydrolysis reactions) phase II enzymes (conjugation reactions with glutathione, glucuronic acid, methyl groups, acyl groups, acetyl residues, amino acids or sulfate groups) and phase III transporters (multidrug resistance-related transporters). Specific pharmacological interventions in the activity of these enzymes and transporters can sensitize tumors to chemotherapy.

There is a large variety of chemosensitizing agents reported in the literature affecting pharmacodynamic processes in tumor cells. They can be summarized according to the drug resistance mechanisms that they attack in tumors:

• Chemosensitizers of drug-target site mechanisms. A basic principle of targeted cancer therapy is to inhibit a tumor-specific or at least tumor-related cellular structure. Although numerous targeted drugs have been approved for cancer therapy in the past, it turned out that tumor cells still can survive by specific resistance mechanisms. Therefore, chemosensitizers of drug-target site mechanisms are needed, e.g., DNA repair inhibitors, inhibitors of specific target proteins, redox modulators, chemosensitizers of endocrine resistance, chemosensitizers of resistance towards tyrosine kinase inhibitors, epigenetic inhibitors, aptamers, therapeutic nucleic acids).
• Chemosensitizers of resistance mechanisms operating upstream of the actual drug target. Chemosensitizers of upstream mechanisms include inhibitors of P-glycoprotein and other ABC transporters, inhibitors of microenvironment-mediated drug resistance, and chemosensitizers for drug-resistant cancer stem cells).
• Chemosensitizers of resistance mechanisms operating downstream of the actual drug target. Even if a suitable target in tumor cells has been successfully inhibited by a cancer drug, the cancer cells eventually may not die, because the death machinery is blocked. Chemosensitizers of downstream mechanisms include inhibitors of negative regulators in apoptosis, autophagy and other modes of programmed cell death).

There is an increasing arsenal of powerful high-throughput screening techniques to identify novel chemosensitizers to overcome cancer drugs resistance. To complete this book on chemosensitizers, another 2–3 chapters on technical approaches to identify chemosensitizing agents will be added.

Prof. Dr. Thomas Efferth
Guest Editor

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