Hybrid Drugs—A Strategy for Overcoming Anticancer Drug Resistance? (original) (raw)
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Concept of Hybrid Drugs and Recent Advancements in Anticancer Hybrids
Pharmaceuticals, 2022
Cancer is a complex disease, and its treatment is a big challenge, with variable efficacy of conventional anticancer drugs. A two-drug cocktail hybrid approach is a potential strategy in recent drug discovery that involves the combination of two drug pharmacophores into a single molecule. The hybrid molecule acts through distinct modes of action on several targets at a given time with more efficacy and less susceptibility to resistance. Thus, there is a huge scope for using hybrid compounds to tackle the present difficulties in cancer medicine. Recent work has applied this technique to uncover some interesting molecules with substantial anticancer properties. In this study, we report data on numerous promising hybrid anti-proliferative/anti-tumor agents developed over the previous 10 years (2011-2021). It includes quinazoline, indole, carbazole, pyrimidine, quinoline, quinone, imidazole, selenium, platinum, hydroxamic acid, ferrocene, curcumin, triazole, benzimidazole, isatin, pyrrolo benzodiazepine (PBD), chalcone, coumarin, nitrogen mustard, pyrazole, and pyridine-based anticancer hybrids produced via molecular hybridization techniques. Overall, this review offers a clear indication of the potential benefits of merging pharmacophoric subunits from multiple different known chemical prototypes to produce more potent and precise hybrid compounds. This provides valuable knowledge for researchers working on complex diseases such as cancer.
1999
The focus of drug development has moved from cytotoxic compounds identified by screening to therapies that act at specific molecular targets. Although some of these agents may cause visible tumor reduction and may be adequately evaluated by standard oncology drug development methods, other novel therapies may not be amenable to our current practices. Consequently, our concepts of drug development must evolve and address various questions. How should we approach the preclinical development of these agents? Which laboratory experiments are critical prior to studying these new agents in the clinic? What phase I design strategies are appropriate? Agents that target specific molecules may not cause toxicity at effective doses and, therefore, phase I concepts such as maximum tolerated dose (MTD) may not be relevant. What phase II designs suit these agents? Drugs that have a cytostatic effect may be overlooked if tumor response is required as a selection criteria. Phase II studies may not be necessary if the relevant end point is survival, which cannot be fully addressed without a large randomized phase III trial. What can we learn from other areas of medicine? Many nononcology drugs target specific end points and are developed in a pattern quite different from the formula used in oncology. Should we be adopting their methods of drug development? At the 10th National Cancer Institute-European Organization for Research and Treatment of Cancer Symposium on New Drugs in Cancer Therapy, a workshop discussed these issues. In this commentary, we summarize some of the presentations. Although many new agents are entering or are already in clinical trials, it is imperative that we continue this dialogue with scientists, clinical researchers, cooperative groups, and industry and regulatory authorities because there is not yet an international consensus on how to approach the challenges that lie ahead.
Rationale and clinical use of multitargeting anticancer agents
Current Opinion in Pharmacology, 2013
Human solid tumors contain genetically distinct subpopulations of tumor cells that can be enriched under selective pressure of specific treatments. This heterogeneous nature reflects the dynamism of drug response and it represents a fundamental driver of resistance. Moreover, the complexity of cancer disease is increased by the activity of cross-talking, redundant signaling pathways, escape pathways and compensatory events, which triggers activation of secondary growth and survival. Broad multi-targeted approaches are requested to overcome a complex, heterogeneous, and dynamic disease such as cancer.
European Journal of Medicinal Chemistry, 2014
A Hybrid drug which comprises the incorporation of two drug pharmacophores in one single molecule are basically designed to interact with multiple targets or to amplify its effect through action on another bio target as one single molecule or to counterbalance the known side effects associated with the other hybrid part. The present review article offers a detailed account of the design strategies employed for the synthesis of anticancer agents via molecular hybridization techniques. Over the years, the researchers have employed this technique to discover some promising chemical architectures displaying significant anticancer profiles. Molecular hybridization as a tool has been particularly utilized for targeting tubulin protein as exemplified through the number of research papers. The microtubule inhibitors such as taxol, colchicine, chalcones, combretasatin, phenstatins and vinca alkaloids have been utilized as one of the functionality of the hybrids and promising results have been obtained in most of the cases with some of the tubulin based hybrids exhibiting anticancer activity at nanomolar level. Linkage with steroids as biological carrier vector for anticancer drugs and the inclusion of pyrrolo [2,1-c] [1,4]benzodiazepines (PBDs), a family of DNA interactive antitumor antibiotics derived from Streptomyces species in hybrid structure based drug design has also emerged as a potential strategy. Various heteroaryl based hybrids in particular isatin and coumarins have also been designed and reported to posses' remarkable inhibitory potential. Apart from presenting the design strategies, the article also highlights the structure activity relationship along with mechanistic insights revealed during the biological evaluation of the hybrids.
Key genes and drug delivery systems to improve the efficiency of chemotherapy
Cancer Drug Resistance, 2020
Cancer cells can develop resistance to anticancer drugs, thereby becoming tolerant to treatment through different mechanisms. The biological mechanisms leading to the generation of anticancer treatment resistance include alterations in transmembrane proteins, DNA damage and repair mechanisms, alterations in target molecules, and genetic responses, among others. The most common anti-cancer drugs reported to develop resistance to cancer cells include cisplatin, doxorubicin, paclitaxel, and fluorouracil. These anticancer drugs have different mechanisms of action, and specific cancer types can be affected by different genes. The development of drug resistance is a cellular response which uses differential gene expression, to enable adaptation and survival of the cell to diverse threatening environmental agents. In this review, we briefly look at the key regulatory genes, their expression, as well as the responses and regulation of cancer cells when exposed to anticancer drugs, along with the incorporation of alternative nanocarriers as treatments to overcome anticancer drug resistance.
Improving Targeted Small Molecule Drugs to Overcome Chemotherapy Resistance
Conventional cancer treatments face the challenge of therapeutic resistance, which causes poor treatment outcomes. The use of combination therapies can improve treatment results in patients and is one of the solutions to overcome this challenge. Chemotherapy is one of the conventional treatments that, due to the non-targeted and lack of specificity in targeting cancer cells, can cause serious complications in the short and long-term for patients by damaging healthy cells. Also, the employment of a wide range of strategies for chemotherapy resistance by cancer cells, metastasis, and cancer recurrence create serious problems to achieve the desired results of chemotherapy. Accordingly, targeted therapies can be used as a combination treatment with chemotherapy to both cause less damage to healthy cells, which as a result, they reduce the side effects of chemotherapy, and by targeting the factors that cause therapeutic challenges, can improve the results of chemotherapy in patients. Sma...
Emerging nanotechnology-based therapeutics to combat multidrug-resistant cancer
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Cancer often develops multidrug resistance (MDR) when cancer cells become resistant to numerous structurally and functionally different chemotherapeutic agents. MDR is considered one of the principal reasons for the failure of many forms of clinical chemotherapy. Several factors are involved in the development of MDR including increased expression of efflux transporters, the tumor microenvironment, changes in molecular targets and the activity of cancer stem cells. Recently, researchers have designed and developed a number of small molecule inhibitors and derivatives of natural compounds to overcome various mechanisms of clinical MDR. Unfortunately, most of the chemosensitizing approaches have failed in clinical trials due to non-specific interactions and adverse side effects at pharmacologically effective concentrations. Nanomedicine approaches provide an efficient drug delivery platform to overcome the limitations of conventional chemotherapy and improve therapeutic effectiveness....
Drug Targeting Strategies in Cancer Treatment: An Overview
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Classic chemotherapy has little or no specificity for cancer cells, normally resulting in low accumulation at the tumor region (inefficacy), and in severe side effects (toxicity). This challenge has resulted in the development of several delivery strategies for chemotherapy agents to improve their concentration at the tumor site, simultaneously increasing their anticancer efficacy, while reducing the associated adverse systemic effects. In this work, the potential of drug delivery strategies involving the use of nanocarriers for controlling the biodistribution of antitumor drugs is deeply revised: passive targeting (through the enhanced permeability and retention effect, EPR effect) and active targeting (including stimuli-sensitive carriers and ligand-mediated delivery). Special attention will be also focussed on the recent approaches for overcoming multi-drug resistance. Finally, a general view of the problem of “nanotoxicity” in cancer treatment is also given.