Hybrid Drugs—A Strategy for Overcoming Anticancer Drug Resistance?

Abstract

Despite enormous progress in the treatment of many malignancies, the development of cancer resistance is still an important reason for cancer chemotherapy failure. Increasing knowledge of cancers’ molecular complexity and mechanisms of their resistance to anticancer drugs, as well as extensive clinical experience, indicate that an effective fight against cancer requires a multidimensional approach. Multi-target chemotherapy may be achieved using drugs combination, co-delivery of medicines, or designing hybrid drugs. Hybrid drugs simultaneously targeting many points of signaling networks and various structures within a cancer cell have been extensively explored in recent years. The single hybrid agent can modulate multiple targets involved in cancer cell proliferation, possesses a simpler pharmacokinetic profile to reduce the possibility of drug interactions occurrence, and facilitates the process of drug development. Moreover, a single medication is expected to enhance patient compliance due to a less complicated treatment regimen, as well as a diminished number of adverse reactions and toxicity in comparison to a combination of drugs. As a consequence, many efforts have been made to design hybrid molecules of different chemical structures and functions as a means to circumvent drug resistance. The enormous number of studies in this field encouraged us to review the available literature and present selected research results highlighting the possible role of hybrid drugs in overcoming cancer drug resistance.

The gold complex auranofin: new perspectives for cancer therapy

“…Such hybrid compound would have higher lethality than the individual drugs against cancer cells resistant to standard platinum-based therapy at the time of recurrence. Hybrid compounds simultaneously targeting different points of signaling networks and various structures within cancer cells were explored extensively in recent years [ 145 ]. It has become clear that it is very difficult to achieve desirable chemotherapeutic effects in the treatment of advanced cancers using single drug therapy.…”

The Monoterpenoid Perillyl Alcohol: Anticancer Agent and Medium to Overcome Biological Barriers

“…Some hybrid drugs are generated as multifunctional compounds, where two or more molecules with already well-characterized pharmacologic activity are conjugated through a stable or metabolizable linker. The central rationale of associating these pharmacophores is to increase their potency, to possibly enable overall dosing at lower levels to minimize toxic side effects, and to reduce the likelihood of emerging drug resistance [161,162]. For example, it was investigated [163] whether linking POH to dihydropyrimidinones would generate increased anticancer impact.…”

Natural Product-Based Hybrids as Potential Candidates for the Treatment of Cancer: Focus on Curcumin and Resveratrol

“…The synthesis of Cur- and Res-based hybrid compounds represents an innovative approach for drug discovery in the field of anticancer chemotherapy. This strategy is based on the possibility to connect, via covalent chemical bonds, two or more bioactive scaffolds endowed with pharmacological activity [ 6 , 45 , 46 , 47 ] so that the fusion of different pharmacophores in a new multifunctional compound is aimed to obtain a better efficacy in comparison with the parent drugs in terms of improved pharmacokinetic and pharmacodynamic properties and decreased toxicity [ 45 ] ( Table 1 and Table 2 ).…”

“…The synthesis of Cur-and Res-based hybrid compounds represents an innovative approach for drug discovery in the field of anticancer chemotherapy. This strategy is based on the possibility to connect, via covalent chemical bonds, two or more bioactive scaffolds endowed with pharmacological activity [6,[45][46][47] so that the fusion of different pharmacophores in a new multifunctional compound is aimed to obtain a better efficacy in comparison with the parent drugs in terms of improved pharmacokinetic and pharmacodynamic properties and decreased toxicity [45] (Tables 1 and 2). For example, to overcome the negative physicochemical properties of Cur, some Curbased hybrids have been projected starting from Cur monocarbonyl analogs by deleting the reactive β-diketone moiety, which is an unfavorable feature for the real bioavailability of this polyphenol (e.g., [58,59]).…”