Anticancer Hybrid Combinations: Mechanisms of Action, Implications and Future Perspectives

The exponential growth of cancer cases worldwide together with recent advances concerning the pathophysiological mechanisms of the disease at the molecular level led to a paradigm shift in chemotherapy, from monotherapy to targeted drug combination regimens. However, adverse effects and the emergence of multidrug resistance (MDR) limit the effectiveness of these therapies. In this context, hybrid combinations mixing anticancer drugs and bioactive phytochemical components from medicinal plants, or even plant extracts, that can act synergistically on multiple targets and signaling pathways represent a promising approach with the potential to expand the current therapeutic arsenal. This review aims to provide a synopsis on anticancer hybrid combinations based on their multi-target mechanisms and synergistic effects from an extensive literature search focusing mainly on publications from the last ten years. In most of these combinations, the phytochemical component was shown to enhance the anticancer activity of the chemotherapeutic agent and to sensitize chemoresistant tumors in several types of cancer. Hybrid combinations, due to synergistic interactions, are also associated with less severe adverse events since lower doses can be used to achieve the same therapeutic effect. Further preclinical and clinical studies are needed, as well as the development of an adequate regulatory framework, before hybrid combination therapy can be translated into clinical practice.