Finding potent multidrug combinations against cancer and infections is a pressing therapeutic challenge; however, screening all combinations is difficult because the number of experiments grows exponentially with the number of drugs and doses.
Chemotherapy fails to cure most cancer patients with advanced disease, particularly patients with the most common forms of solid tumors. The presence or development of resistance to anticancer agents is the major cause of this failure. Several of the mechanisms underlying drug resistance to cytotoxic drugs have been elucidated in the last two decades, largely by employing in vitro drug-selected cancer cell lines. In unselected cell lines and probably also in human cancer, multiple mechanisms are redundantly present to defend the organism from the insults of drugs. Mechanisms have been unraveled by which cross-resistance ensues to multiple drugs (multidrug resistance), similar to what is commonly seen in patients. More recently, the identification of downstream genes, intimately involved in cell-cycle checkpoints, appears also to directly contribute to determining the sensitivity to cytotoxic drugs by regulating the response of the cell to the drug
Drug activation in vivo involves complex mechanisms in which substances interact with different proteins. These interactions can modify, partially degrade, or complex the drug with other molecules or proteins, ultimately leading to its activation. Many anticancer drugs must undergo metabolic activation in order to acquire clinical efficacy. However, cancer cells can also develop resistance to such treatments through decreased drug activation.
Alteration of Drug Targets
A drug’s efficacy is influenced by its molecular target and alterations of this target, such as mutations or modifications of expression levels. In cancers, these types of target alterations can ultimately lead to drug resistance. For example, certain anticancer drugs target topoisomerase II, an enzyme that prevents DNA from becoming super- or under-coiled. The complex between DNA and topoisomerase II is usually transient, but these drugs stabilize it, leading to DNA damage, inhibition of DNA synthesis, and a halting of mitotic processes. Cancer cells can confer resistance in these circumstances through various means. Certain cell lines have become resistant to topoisomerase II-inhibiting drugs through mutations in the topoisomerase II gene .
One of the most studied mechanisms of cancer drug resistance involves reducing drug accumulation by enhancing efflux. Members of the ATP-binding cassette (ABC) transporter family proteins enable this efflux and are important, well-studied regulators at the plasma membranes of healthy cells. ABC transporters are transmembrane proteins present not only in human cells, but in all extant phyla, functioning to transport a variety of substances across cellular membranes.
DNA Damage Repair
The repair of damaged DNA has a clear role in anticancer drug resistance. In response to chemotherapy drugs that either directly or indirectly damage DNA, DNA damage response (DDR) mechanisms can reverse the drug-induced damage. For example, platinum-containing chemotherapy drugs such as Cisplatin cause harmful DNA crosslinks, which can lead to apoptosis. However, resistance to platinum-based drugs often arises due to nucleotide excision repair and homologous recombination, the primary DNA repair mechanisms involved in reversing platinum damage.
Cell Death Inhibition
Cell death by apoptosis and autophagy are two important regulatory events. Although these processes are antagonistic to one another, they both contribute to cell death. Apoptosis has two established pathways: an intrinsic pathway mediated by the mitochondria that involves B-cell lymphoma 2 (BCL-2) family proteins, caspase-9 and Akt, and an extrinsic pathway that involves death receptors on the cell surface. The intrinsic and extrinsic pathways merge through the activation of down-stream caspase-3, which ultimately causes apoptosis.
Cancer Cell Heterogeneity
In addition to the development of drug resistance in cancer progenitor cells and adult cancer cells by the mechanisms previously discussed, another aspect of cancer relapse is the enrichment of drug resistant cancer cells already present in the heterogeneous cancer cell population. Recent studies show that a fraction of cells within this heterogeneous population have stem cell properties and are usually drug resistant.
Cancer drug resistance is a complex phenomenon that is influenced by drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition, EMT, inherent cell heterogeneity, epigenetic effects, or any combination of these mechanisms. The current paradigm states that combination therapy should be the best treatment option because it should prevent the development of drug resistance and be more effective than any one drug on its own.
These drug resistant cancer cells also contribute to cancer relapse after apparent remission. It will be interesting to determine how much contribution cancer progenitor cells or drug resistant cancer cells render to generate drug resistance. Therefore, it is important to continue efforts to understand the underlying mechanisms of cancer drug resistance and to identify therapies that can treat cancers no longer susceptible to current treatments