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Clinical Biochemistry Nessar Ahmed. Foresight Marcos Eberlin. Ingredient Ali Bouzari. Protein Downstream Processing Nikolaos Labrou. Food Chemistry H. In order to overcome drug resistance of MMSCs and develop innovative strategies, mechanisms of drug resistances strongly need to be clarified. These transporter proteins use the energy from ATP hydrolysis to efflux cytotoxic compounds across the membrane, which is believed to be one of the major causes of multidrug resistance in cancer therapy [ 45 ].
Hawley et al. Hirschmann-Jax et al. ALDH aldehyde dehydrogenase catalyzes the chemical transformation from acetaldehyde to acetic acid. Upregulation of ALDH expression has been detected in normal adult stem cells. ALDH is commonly deregulated in many tumors. Increased expression of ALDH in cancer is associated with increased stemness and poor clinical outcome [ 21 , 50 - 54 ]. More recently, we demonstrate that member A1 of the ALDH1 family of proteins, ALDH1A1, was up-regulated in the course of myeloma therapy and progression, and that enforced expression of ALDH1A1 led to both increased tumorigenicity and resistance to two widely used myeloma drugs doxorubicin, bortezomib in vitro and in vivo [ 56 ].
When CSCs were treated with certain chemotherapy agents, they produced toxic aldehyde intermediates. ALDH could detoxify these toxic aldehyde intermediates. Raha et al. Chemotherapeutic agents function by inducing apoptosis.
Oncotarget | Multiple myeloma cancer stem cells
The balance of pro- and anti-apoptotic proteins affected the apoptotic response of cells to these chemotherapeutic agents. Increased expression of anti-apoptotic proteins and decreased expression of pro-apoptotic proteins confer cells drug resistance. Cellular quiescence is a property of hematopoietic stem cells and is thought to play a crucial role in protecting stem cells [ 60 ]. Similar to normal stem cells, CSCs have a slow cycling rate and are relatively quiescent.
This property protects CSCs against chemotherapeutic agents that are effective in targeting all dividing cells [ 58 ]. This property has been conjectured to be a major mechanism of drug resistance. These results are consistent with Fuhler et al. Further research showed that Pre-PCs were more quiescent than PCs, revealed by the lower proportion of Pre-PCs in S phase of cell cycle, suggesting that cellular quiescence may be involved in drug resistance. The above findings imply that MMSCs resistant to chemotherapeutics may be mediated by cellular quiescence. Hedgehog Hh pathway is typically active in hematopoietic stem cells and CSCs [ 63 ].
The Notch pathway promotes CSCs [ 64 , 65 ].
Animal Models of T-Cell Mediated Skin Diseases - Ernst Schering Research Foundation Workshop 50
Increased evidence demonstrates that targeting these pathways individually will not be sufficient to kill MMSCs; instead, rational combinations of agents targeting these pathways in concert could be of particular importance. The Wnt signaling pathway plays a significant role in the regulation of cell proliferation, cell development and the differentiation of normal stem cells. Constitutive activation of Wnt signaling pathway is found in a variety of human cancers [ 67 , 68 ]. MM cells have been reported to depend on an active Wnt signaling.
The dysregulation of Wnt signaling pathways resulted in promoting MM cell proliferation, migration, invasion, drug resistance and formation of MMSCs [ 46 ]. Sukhdeo et al.