Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • br Mechanisms of anticancer drug resistance

    2018-10-25


    Mechanisms of anticancer drug resistance Tumor resistance to anticancer drug was a well-known clinical phenomenon that was yielding its secrets to investigation at the molecular level. It was important to validate the important mechanisms from the resistance situation of the patient. Table 2 shows the resistance mechanisms and the potential effective agents in anticancer therapy. Several mechanisms involved in resistance to anticancer drug, including an increase in drug efflux, alteration or mutation of drug targets, drug detoxification and inactivation, impact on apoptosis, interference with DNA replication and many other ways.
    Expression of drug efflux pumps One of the main causes for the failure of cancer therapy was multidrug resistance (MDR). MDR occurred at the beginning of the treatment or during treatment when Romidepsin resist to the treatment. One of the mechanisms was the increased expression of drug efflux pumps, such as P-glycoprotein (P-gp). P-gp was one of the ATP-binding cassette (ABC) transporters and was encoded by the MDR1 (ABCB1) gene. A previous study has revealed that over 96% of cells expressed P-gp in colorectal cancer. P-gp serves an important role in the generation and maintenance of colorectal cancer drug resistance. P-gp became a target of several studies to identify novel compounds to counteract MDR. Wang S et al. reported MRP1 acted as an efflux pump, which rapidly extruded various anticancer drugs from the targeted cancer cells. Azzariti A et al. suggested that both Gefitinib and Vandetanib may act as inhibitorsof P-gp and transported substrates for Breast Cancer ResistanceProtein (BCRP, ABCG2). Short periods of exposure to TKIs could provide insights into the nature of the binding to MDR-relatedproteins, either as inhibitors or assubstrates, The analysis of exposure periods was needed in order to optimise future development in combination with established chemotherapeutic approaches. It has also been reported that aberrantly regulated Wnt/beta-catenin and Notch1 signaling in carcinoma stem cells (CSCs) were involved in MDR. The MDR properties of CSC were due to the overexpression of the ABC transporter protein ABC sub-family G member 2 (ABCG2), which acted as a drug efflux pump for Romidepsin DNA-targeting drugs. Some researchers also studied the mechanisms responsible for the onset ofresistanceto drug therapy by EGFR inhibitors such as TKIs. Among ABC transporters involved in MDR, P-gp and BCRP have been considered as the pumps responsible for TKIs treatment failure, including gefitinib and erlotinib. Moreover, two subtypes of EGFR mutations have been described: mutations of the exons coding for tyrosine kinase domain (18 to 21) and truncating mutations (exons 2 to 7) that involved downstream effectors such as MAPK, PI3K/Akt and STAT. The first group of mutations could be considered as a hallmark of NSCLC and were responsible for the failure of TKIs while the second group of mutations led toresistance. Galetti M et al. indicated that gefitinib inhibited ABCG2 activity in lung cancer cells and ABCG2 silencing or overexpression affects intracellular gefitinib content by modulating the uptake rather than the efflux. Overexpression of ABCG2 affected the expression of a number of drug transporters, altering the functional activities of nutrient and drug transport systems.
    Alteration or mutation of drug targets Drug resistance in anticancer therapy could be greatly affected in the molecular level of drug targets. Generally, the mutations of functional targets or some alterations of expression levelsdramatically influenced drug resistance. Recently, new anticancer drugs that targeted oncogenic signaling pathways have been developed. Two representative examples of such drugs were cetuximab and panitumumab, two monoclonal antibodies (moAbs) against the EGFR, which have been proven to be effective for patients with RAS wild type (RAS-WT) metastatic colorectal cancer (mCRC). However, a large part of unselected mCRC patients were not benefit from but resistant to the anti-EGFR therapy. It suggested that the primary resistance to anti-EGFR therapy is common in CRC. Trastuzumab, a recombinant anti-HER2 agent, was the first biological drug approved and remained the gold standard for the treatment of HER2+ BC. Though many studies have proved the satisfactory therapeutic efficacy of trastuzumab, some HER2+ BC patients showed intrinsic or acquired resistance to it. Resistance mechanisms to trastuzumab develop often as a result of HER2 gene amplification or protein overexpression. The increased PI3K signaling and the presence of alternative forms of HER2 are not detected by trastuzumab. The modulation of Cdk inhibitor p27 by insulin-like-growth-factor 1 (IGF-1) may be a key player in resistance to trastuzumab as overexpressed IGF-1 is responsible for the activation of the PI3K downstream signaling pathway and further effects on Akt.