177
Perylenequinones are placed under second generation of cellular photosensitizer,
which are highly valued as potential therapeutic agents in cancer treatment. This
class of compounds possesses a wide range of attributes like good solubility, dark
inactivation, accessible to chemicals modifications, and various others, making it a
good candidate for safe clinical use (Beck et al. 1999; Diwu and Lown 1993).
Calphostin C is a PKC-inhibiting lipophilic perylenequinone isolated from the fungus Cladosporium cladosporioides. Calphostin C specifically and selectively abrogates the function of PKC in a photodependant manner (Bruns et al. 1991). Lamin
B, a component of nuclear lamina, the fibrous region lining the inner areas of nuclear
envelope, is also a target of calphostin C. In the event of illumination, calphostin
travels to cytoplasm and concentrates mainly in the endoplasmic reticulum and
Golgi apparatus leading to stress (Kaul and Maltese 2009). The activated calphostin, owing to its lipophilicity (ability to dissolve in fats), gets accumulated in the
endoplasmic-reticulum-derived cell nuclear envelope but does not gain a direct
entry into nucleus. Investigations have revealed that in the first initial 30 min of
illumination, the compound in its active form triggers a progressive decline in lamin
B, which from thereon will completely disappear during the subsequent incubation
in dark for 30 min. In the 30 min of illumination, the activated calphostin in the
cytoplasm will lead to decrease in activity of different cytoplasmic PKC forms (Dal
Pra et al. 2000; Chiarini et al. 2006). At this stage, there will be no initiation of
apoptogenesis due to caspase activation or exit of cytochrome c from mitochondria.
In the event of transfer of cells into dark, the destruction of lamin B1 proceeds to
end. The light-restrained activities of cytoplasmic PKC will regain its functional
activity in the dark. This resurrection of PKC activities will initiate the first steps of
apoptogenesis, leading to mitochondrial cytochrome c release. Caspase activation
will lead to full cellular action, leading to PCD, and roughly more than 90% of the
cells die within duration of 3.5 h after the starting of dark phase. These results
ensure that the light-activated calphostin is necessary for PKC-related actions to
take place in dark and further ensuing in PCD (Chiarini et al. 2006). The presence
of activated calphostin in the cytoplasm leads to intranuclear aggregation of aqueous peroxidase that causes the selective degradation of nuclear envelope (lamin B1).
Target of rapamycin (TOR) is a combination of two structurally separate serine/
threonine kinase enzyme termed TOR complex 1 and TOR complex 2. This enzyme
complex is evolutionary conserved from yeast to mammals, and the mammalian
counterpart is called mammalian target of rapamycin (mTOR) (Wullschleger et al.
2006). The components of mTOR complex have distinct functions with mTORC1
assisting in cell growth through control of protein anabolism, nucleotide biosynthesis, autophagy, glycolysis, and lipogenesis. The mTORC2 is involved in actin cytoskeleton arrangement, glucose metabolism, and lipogenesis (Betz and Hall 2013).
The TOR complex came to light on elucidating the mechanism of action of TOR
inhibitor called rapamycin. Rapamycin is a complex macrolide which is known for
its wide range of roles as antitumor agent, immunosuppressant, and fungicide with
its high specificity to mTOR. Rapamycin was isolated from S. hygroscopicus from
the soil samples collected from Easter Island. It is a white crystalline substance with
less solubility in water and high solubility in organic solvents. Among the two components of mTOR complex, mTORC1 is the primary target of rapamycin. Rapamycin
7 Anti Cancer Agents from Microbes
Perylenequinones are placed under second generation of cellular photosensitizer,
which are highly valued as potential therapeutic agents in cancer treatment. This
class of compounds possesses a wide range of attributes like good solubility, dark
inactivation, accessible to chemicals modifications, and various others, making it a
good candidate for safe clinical use (Beck et al. 1999; Diwu and Lown 1993).
Calphostin C is a PKC-inhibiting lipophilic perylenequinone isolated from the fungus Cladosporium cladosporioides. Calphostin C specifically and selectively abrogates the function of PKC in a photodependant manner (Bruns et al. 1991). Lamin
B, a component of nuclear lamina, the fibrous region lining the inner areas of nuclear
envelope, is also a target of calphostin C. In the event of illumination, calphostin
travels to cytoplasm and concentrates mainly in the endoplasmic reticulum and
Golgi apparatus leading to stress (Kaul and Maltese 2009). The activated calphostin, owing to its lipophilicity (ability to dissolve in fats), gets accumulated in the
endoplasmic-reticulum-derived cell nuclear envelope but does not gain a direct
entry into nucleus. Investigations have revealed that in the first initial 30 min of
illumination, the compound in its active form triggers a progressive decline in lamin
B, which from thereon will completely disappear during the subsequent incubation
in dark for 30 min. In the 30 min of illumination, the activated calphostin in the
cytoplasm will lead to decrease in activity of different cytoplasmic PKC forms (Dal
Pra et al. 2000; Chiarini et al. 2006). At this stage, there will be no initiation of
apoptogenesis due to caspase activation or exit of cytochrome c from mitochondria.
In the event of transfer of cells into dark, the destruction of lamin B1 proceeds to
end. The light-restrained activities of cytoplasmic PKC will regain its functional
activity in the dark. This resurrection of PKC activities will initiate the first steps of
apoptogenesis, leading to mitochondrial cytochrome c release. Caspase activation
will lead to full cellular action, leading to PCD, and roughly more than 90% of the
cells die within duration of 3.5 h after the starting of dark phase. These results
ensure that the light-activated calphostin is necessary for PKC-related actions to
take place in dark and further ensuing in PCD (Chiarini et al. 2006). The presence
of activated calphostin in the cytoplasm leads to intranuclear aggregation of aqueous peroxidase that causes the selective degradation of nuclear envelope (lamin B1).
Target of rapamycin (TOR) is a combination of two structurally separate serine/
threonine kinase enzyme termed TOR complex 1 and TOR complex 2. This enzyme
complex is evolutionary conserved from yeast to mammals, and the mammalian
counterpart is called mammalian target of rapamycin (mTOR) (Wullschleger et al.
2006). The components of mTOR complex have distinct functions with mTORC1
assisting in cell growth through control of protein anabolism, nucleotide biosynthesis, autophagy, glycolysis, and lipogenesis. The mTORC2 is involved in actin cytoskeleton arrangement, glucose metabolism, and lipogenesis (Betz and Hall 2013).
The TOR complex came to light on elucidating the mechanism of action of TOR
inhibitor called rapamycin. Rapamycin is a complex macrolide which is known for
its wide range of roles as antitumor agent, immunosuppressant, and fungicide with
its high specificity to mTOR. Rapamycin was isolated from S. hygroscopicus from
the soil samples collected from Easter Island. It is a white crystalline substance with
less solubility in water and high solubility in organic solvents. Among the two components of mTOR complex, mTORC1 is the primary target of rapamycin. Rapamycin
7 Anti Cancer Agents from Microbes