Anticancer drugs can fail to kill cancer cells for various reasons; one such reason for failure is drug resistance in cancer. Tumours have several mechanisms in which they become multi-drug resistance tumours; I will be focusing on the most common of these mechanisms which is the increased efflux of cytotoxic drugs out of the cell. This occurs due to multi-drug resistance (MDR) efflux transporters which are a member of the family of energy-dependent transporters, known as ATP-binding cassette (ABC) transporters such as P-glycoprotein [Pgp, also known as ABCBl or MDR1). There are many different ABC transporters with main different function such as detoxification and protection against xenobiotics. They have a pivotal role, as they may influence the tissue distribution and bioavailability of drugs, since ABC transporters are greatly expressed in pharmacological barrier, such as the epithelium of the blood brain barrier, the luminal membrane of proximal tubules of the kidney. It is therefore paramount to identify whether a drug can cross the barriers or is restricted by ABC transporters and whether the inhibition of ABC transporters influences the pharmacokinetic of the drug. Example of this is through the study of mice it has been found that absence of the Pgp transported has a huge impact on tissue distribution and oral bioavailability of taxol. By trial studies it is found that several ABC transporters have been over expressed in cancer cells such as small lung cancer cells. It was also shown that the major mechanism of multi-drug resistance involved MRP1 (also known as ABCC1) and ABCG2.
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Apoptosis of tumour cells is the main objective of chemotherapy treatments, as seen in curable malignancies such as leukemia, apoptosis is easily undergone. Apoptosis is mediated by caspase activation; caspases are cysteine proteases which cleave cellular protein resulting in rapid cell death usually by degradation of chromosomal DNA, chromatin and cytoplasmic condensation and nuclear fragmentation. Apoptosis occur through two main pathways extrinsic and intrinsic; they initiate the activation of caspases-8 and caspase-9 leading to the activation of caspase-3 which is the executioner caspase.
Chemotherapy is thereby limited by multi-drug resistance, as the multidrug resistance associated protein (MRP) and P-glycoprotein (Pgp) reduce the intracellular concentration of drug by efflux from cell. To overcome this problem trials have been done, one such study showed the possibility of protecting normal cells but not multidrug-resistant cells against the cytotoxicity of chemotherapeutic agents , by effective combinations that discriminate normal vs. Pgp- and MRP-expressing cells. This is done with a combination and requirements of a caspase inhibitor (cytoprotective) which inhibits apoptosis caused by the chemotherapeutic agents and is a substrate of Pgp and MRP and chemotherapeutic agents (cytotoxic) which induces apoptosis and is full active against Pgp and MPR expressing cell.
The ABC transporter pumps molecules out according to their structure, not their function; this means MDR may be resistant to cytoprotective agents as well as cytotoxic agents, and we can use this to exploit multi-drug resistance. We can also treat other condition in animal model in which apoptosis is bad such as auditory sensory damage from cisplatin by using caspase inhibitor, Ac-VAD, Z-DEVD-fmk, and B-D-fmk. Inhibition of caspases can be used for treatment of stroke, sepsis and meningitis. The use of caspase inhibitor in multi-drug resistance tumour may seem too be contraindicated, as activation of apoptosis is desired, not the inhibition but the use of caspase inhibitors can be used to protect normal cell whilst using chemotherapeutic agents.
Figure1. (A) Using an exclusive protector molecule that is a substrate of multidrug-resistance pumps (and therefore protects normal cells but not cancer cells) and an inclusive anticancer drug that is not a substrate of Pgp or MRP, cancer cells can be selectively killed with normal cells being spared. (B) The caspase inhibitor Z-DEVD protects normal cells (left) from the inclusive cytotoxic agent Flavopiridol (FP). Cancer cells (right) pump the protective agent out and are killed by FP.
Since drug efflux is according to chemical structure, not the biological function of the substrate, it is therefore possible to use cytoprotective agents which only accumulate in normal non-resistant cells. The cytoprotective agents must be substrate of multidrug resistance pumps (an exclusive protector), and the anticancer drug should not be a substrate of Pgp or MRP (an inclusive drug). Thereby multidrug resistant (MDR) cancer cells pump out the cytoprotective drug making it vulnerable to cytotoxic drug (Fig. 1).
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Caspase inhibitors can be used as the cytoprotective agents because in both normal and cancer cells, cell death is mediated by caspases, and selectively inhibiting caspase will protect any normal cells from anticancer agents. The combination of a caspase inhibitor and a cytotoxic agent should meet four requirements: the cytotoxic agent must induce apoptosis and not be a substrate of the Pgp pump, whereas the caspase inhibitor must block cell death caused by the cytotoxic agent and be a substrate of the pump. An example of these is a combination of the cytotoxic agent flavopiridol and caspase inhibitor Z-DEVD-fmk.
Flavopiridol a cyclic dependent-kinase inhibitor, it is an inducer of apoptosis and is not a substrate of Pgp or MRP, it causes caspase-dependent cell death in cancer cells, the caspase inhibitor Z-DEVD-fmk can protect normal cells from flavopiridol, but fails to protect MRP- and Pgp-expressing cells from flavopiridol. For the caspase inhibitor to be useful it must inhibit caspase induced apoptosis by the cytotoxic drug (flavopiridol) and must be pumped out by the MDR transporters therefore Z-DEVD-fmk showed both effectiveness and exclusivity compared to other caspase inhibitor such as BD-fmk and Z-VAS-fmk which protected normal and MRP expressing cells (Fig.1). Limitation to this study is that these result where carried out in vitro and it is not know how combination therapy might effects the body, especially in other cells which express Pgp transporters such as the blood brain barrier, they will not be protected. Other limitation are that tumour cells are heterogenous, drug-resistant cells are together with non-resistant tumour cells, thus if only this treatment is used non-resistant cancer cells will be spared, It therefore necessary to use conventional non-selective chemotherapy in conjunction