The previous in vitro analyses on cultured endothelial and leukemic T-cells confirmed its therapeutic check details potential both as an antiangiogenic and anticancer agent [1], [2]. Prolonged exposure to in vitro effective doses of PMC was previously shown to decrease cell viability and trigger caspase-dependent apoptosis [2]. PMC-induced cell death was demonstrated to be mediated by activation of both stress-related kinases p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) while extracellular regulated kinase (ERK) activity was reported to significantly decrease upon exposure to the agent. Although a transient intracellular calcium increase was reported to follow PMC exposure in cultured pulmonary endothelial cells, this phenomenon was not synchronized with either endothelial dysfunction or cell death [1].

Physical or chemical environmental stresses including radiation, osmotic stress, and oxidative stress or cell surface receptor ligands such as growth factors, inflammatory cytokines or death receptor ligands may activate a kinase cascade which eventually stimulates stress-activated MAPKs p38 and JNK. Upstream serine/threonine kinases MAP kinase kinase kinases (MEKKs) and MAP kinase kinases (MKKs) are responsible for activation by phosphorylation and subsequent nuclear translocation of JNK and p38 [3]. Once activated, JNK and p38 are known to be capable of apoptotic modulation through activating/deactivating a series of transcription factors.

Apoptosis is a tightly regulated cell death mechanism which is activated in response to various intra-/extracellular stimuli such as oxidative stress and electromagnetic radiation that damage cellular macromolecules or signals including inflammatory cytokines and growth factors. Apoptotic execution is assumed by a family of cysteine proteases called caspases that are activated in a well-defined manner [4]. While the intrinsic pathway is triggered by apoptogenic molecule release from mitochondria, the extrinsic pathway is activated through ligand binding to death receptors on the cell surface. Whether the intrinsic or extrinsic apoptotic pathway will be in action is generally determined by the nature of the stimulus. Independent of the pathway that was activated initially, both the intrinsic and extrinsic pathways could be involved to amplify the apoptotic signal in different circumstances. Cytochrome c release from mitochondria which marks the point of no return for intrinsic apoptotic activity Carfilzomib is intricately regulated by interactions among Bcl-2 family of proteins. The delicate balance between the anti- and proapoptotic members of the family determines the apoptotic load within the cell.