Many Chemotherapeutic Drugs Are Ineffective In Case Of Multiple Myeloma

INTRODUCTION

In the apoptosis process of cancerous cells, cytokines have a big role. The mode of action of these cytokines is via MAP kinase pathway. Upon hup0regulation of mitogen activated protein kinase pathway the vital biological pathways like cellular growth, proliferation and apoptosis are disturbed. The inhibitors to MAP kinases are one of the powerful tools in the era of cancer research. During chemical libraries screening Tipifarnib was discovered as a strong and specific inhibitor of farnesyl-transferase enzyme.

TIPIFARNIB EFFECTS ON IFN-

Interferon- affects on EGF or epidermal growth factor which lead to the activation of MAPK pathway via activation of Ras kinase. This is vital for the cell survival. When a combination of IFN and FTI (farnesyl-transferase inhibitor) was used ceases the tumor growth and triggered the cell death by apoptosis. The proliferation was also suppressed and proapoptotic signals were generated. The effect of this combination resulted in the Ras and ERK activation as stimulated by interferon- and the decrease in the Akt was also observed. Bcl-2 is activated by the action of Raf-1 and then downstream Ras is activated by this mechanism. The Bcl-2 is activated by the phosphorylation of Bad. The function of IFN- was observed as it localized the Raf-1 on mitochondria. The antagonist of this process is Tipifarnib. Interferon- triggers the bcl-2/Raf complex formation. The ser 122 was also phosphorylated by this process. Tipifarnib opposed these all actions. These findings shows the IFN- is an apoptosis inhibitor as it controls survival pathways. The intracellular pathways which were isoprnylation dependent were inhibited by this inhibitor [1].

TIPIFARNIB TRIGGERS APOPTOSIS

Many chemotherapeutic drugs are ineffective in case of multiple myeloma (MM) and leukemia. When a combination of Bortezomib which is a proteasomal inhibitor and Tipifarnib used diminished the drug resistance and suppressed the cancerous growth. The effect of these inhibitor s was synergistic. The studies on 8226 and U937 cell lines were reported where free calcium ions was increased due to Tipifarnib. These calcium ions in turn dynamically stimulated the plasmalemmal region blebbing which leads to the plasma membrane lysis. The inhibition of calcium ions results in the cell death blockage. These findings showed the connection between the Tipifarnib and apoptosis is managed by the calcium ions. In addition to these results the Tipifarnib also acted on the transmembrane channels for the Ca ions which promote the incoming of the Calcium ions [2].

TIPIFARNIB AND GEMCITABINE IN COMBINATION

Cell lines of pancreas are famous for the strong resistance against chemotherapeutic agents. When a combination of Gemcitabine and Tipifarnib was administerd it was found that Gemcitabine enhances the survival rates. This combination was safe to use and tolerated well. The survival time of pancreatic cell lines was not prolonged with these inhibitors [3]. There are other proteins which are also inhibited in addition to Ras by Tipifarnib. The leukemia cell lines were also analyzed for the studies of genes of various important proteins involved in the survival of cells. These genes were tested for the action of Tipifarnib. It was found that this compound was so efficient in the inhibition of many important genes and this resulted in the malfunctioning of certain genes responsible for the processes like immunity, cell signaling, cellular proliferation, cytoskeleton organization as well as apoptosis.

CONCLUSION

In a nut shell, Tipifarnib have broad spectrum effects on the tumor and cancers of specific organs like liver. This kinase inhibitor also targets the vital processes controlled by the various cytokines. By different mechanistic approaches this is one of the potent compounds that triggers the apoptosis via blocking certain important proteins or enzymes.