The Cell - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 32

necrosis, which is different from apoptosis. Apoptosis causes the cell to reduce in
size by shrinking, and its cytoskeletal network also is dismantled. There are surface-
bound changes that induce phagocytosis by macrophages. Therefore, the dying cell
does not spill its content but instead is taken up by the phagocytic cells, and the
organic contents are recycled.
Apoptosis is mediated by a family of proteolytic enzymes called caspases. They
are present in the intracellular compartment as procaspases and are activated when
the signals for apoptosis are generated. The caspases generate an amplifying cascade
of proteases in sequence to bring about the proteolysis of important proteins. The
cell tends to disassemble its cellular machinery, and the cellular remains are engulfed
by the macrophages. But once the cell progresses on the path of death, its reversal or
halting is not feasible. Hence, an efficient control system ensures appropriate timing
for cell death. The control system keeps in check the caspase activity by mediating
through the Bcl-2 family of proteins. The members of the family are either activators
or repressors for procaspase. The two important death-activating members of the Bcl-
2 family are Bak and Bax. They mediate their actions through a pathway involving
cytochrome c released from mitochondria. Bcl-2 and other members of the family
inhibit the activation of procaspase, and hence cell death occurs.
To evade apoptosis, the cells in an organism require trophic factors, survival fac-
tors like mitogens so as to survive and grow. A number of extracellular signals pro-
duced by other cells are known to influence cell proliferation, growth, and death. For
example, mitogens increase the cell proliferation rate by overcoming the molecular
break at the G1/S checkpoint to advance the cell into synthetic phase. In a similar
fashion, the extracellular growth factors increase the biosynthetic activities in the cell
and bring about cellular growth. They ensure that the cell grows and attains an ade-
quate size before the next cycle of division. Cellular growth can also be influenced
by certain extracellular proteins that inhibit the biosynthetic activities and cell divi-
sion, and negate the effects of positive regulatory proteins [10-10] .
1.9 Transporters
These are membrane proteins with a function to ease the movement of substances in
and out of the cell. They are intended for transport of endogenous materials like nutri-
ents, but these proteins are also involved in trafficking drug molecules due to their
structural similarity to endogenous substrates. Drug transporters can consequently
influence their bioavailability, distribution pattern, excretion, toxicity, and so on. A
thorough insight into these different transporters provides a rational scientific basis
for predicting a drug's behavior in the body. Transporters have been under systematic
scientific scrutiny to ascertain their structure, expression, and characterization. These
membrane proteins are known to be amphoteric in nature. Their hydrophobic por-
tions are associated with membrane phospholipids, and hydrophilic surface area is in
contact with aqueous sol, both intracellular and extracellular. The movement of sub-
strates follows different mechanisms and can be categorized as facilitated or passive
transport and active transport. Passive processes exploit an electrochemical gradient