Abstract
Chemotherapeutic drugs target a physiological differentiating feature of cancer cells as they tend to actively proliferate more than normal cells. They have well-known side-effects resulting from the death of highly proliferative normal cells in the gut and immune system. Cancer treatment has changed dramatically over the years owing to rapid advances in oncology research. Developments in cancer therapies, namely surgery, radiotherapy, cytotoxic chemotherapy and selective treatment methods due to better understanding of tumor characteristics, have significantly increased cancer survival. However, many chemotherapeutic regimes still fail, with 90% of the drug failures in metastatic cancer treatment due to chemoresistance, as cancer cells eventually develop resistance to chemotherapeutic drugs. Chemoresistance is caused through genetic mutations in various proteins involved in cellular mechanisms such as cell cycle, apoptosis and cell adhesion, and targeting those mechanisms could improve outcomes of cancer therapy. Recent developments in cancer treatment are focused on combination therapy, whereby cells are sensitized to chemotherapeutic agents using inhibitors of target pathways inducing chemoresistance thus, hopefully, overcoming the problems of drug resistance. In this review, we discuss the role of cell cycle, apoptosis and cell adhesion in cancer chemoresistance mechanisms, possible drugs to target these pathways and, thus, novel therapeutic approaches for cancer treatment.
Highlights
Chemotherapy remains the major treatment in cancer therapy, the molecular mechanisms causing sensitivity or resistance to chemotherapeutic drugs in different tumor types are still unclear
In this review we focus on three main mechanisms involved in chemoresistance, alterations of which we believe will play an important role in improving the effectiveness of cancer therapy
The MK2 pathway has been less studied compared to p38, some data suggest that the MK2 inhibitor MK2.III increases the sensitivity of pancreatic cancer cells to gemcitabine [111], and recent data show that MK2 knockdown reduces in vivo growth of multiple myeloma in mouse models with MK2 overexpression leading to bortezomib and doxorubicin chemoresistance by reducing apoptosis [112]
Summary
Chemotherapy remains the major treatment in cancer therapy, the molecular mechanisms causing sensitivity or resistance to chemotherapeutic drugs in different tumor types are still unclear. Most chemotherapeutic agents cause DNA damage and activate a complex signaling network resulting in cell cycle arrest and/or apoptosis. When DNA damaging agents are used to treat cancer, some clones within the cancer tissue up-regulate the expression of specific genes that either activate, or suppress, signaling networks regulating cell cycle arrest or DNA repair. These alterations may result in resistance of cells to drug-induced death signals. In this review we focus on three main mechanisms involved in chemoresistance, alterations of which we believe will play an important role in improving the effectiveness of cancer therapy
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