176
Arenicolide is a type I polyketide produced by the marine actinomycetes
Salinispora arenicola. The microbe was isolated from marine sediment samples collected from the island of Guam. At an IC 50 touching 30ug/mL the compound arenicolide A showed cytotoxicity toward human colon adenocarcinoma cell line
HCT-116 (Williams et al. 2007). Saliniketal A and B are two other polyketides
sourced from the same strain of actinomycetes. Saliniketal inhibits the expression of
ornithine decarboxylase (ODC). ODC is highly expressed in many cancers and
remains as a major focus for chemoprevention of cancer (Gerner and Meyskens
2004). Chalcomycin is a macrolide with antitumor potential produced by Streptomyces
sp. M491 isolated from samples collected from Qingdao, coastal region of China.
Compounds similar to Chalcomycin were isolated from another Streptomyces strain
B7064 found from mangrove sediments in Hawaii (Asolkar et al. 2002).
7.3
Antitumor Agents and Mechanism of Action
Knowledge of the mechanism undertaken by an agent to kill cancer cells will help in
getting a picture of the possible events that will undergo after the therapy is started. It
will also help in allowing structural modification of the drug, thereby increasing specificity, efficiency, and safety. The mechanism of action employed by the drug will pave
way for understanding the reasons as to why a particular side effect has occurred in
response to a drug. Combinational chemotherapies will be successful when two drugs
can complement each other’s drawbacks, but for a successful combination the actionmechanism of both drugs should be well researched to avoid any adverse effects.
Actinomycin D was the first and oldest microbial metabolite to be approved for
treatment of cancer. Actinomycin A is a close relative of actinomycin D; it was isolated from Streptomyces antibioticus. Actinomycin has a cyclic polypeptide structure
that helps it to selectively bind DNA and block transcription (Reich and Goldberg
1964; Goldberg et al. 1962). This transcription-inhibiting property helps by interfering with the function of RNA polymerase. In particular, transcription at ribosomal
level is found to be most sensitive to the action of actinomycin (Perry 1963). The
initial x-ray crystallography study of actinomycin-deoxyguanosine complex stated a
possible three-dimensional structure of actinomycin binding to DNA. Based on this
study, it was highly believed that the phenoxazone ring present in actinomycin positions into the space between adjacent base pairs and the pentapeptide chain in the
B-helix narrow groove. The formation of hydrogen bonds takes place with guanine
residues in the opposite chain (Sobell et al. 1971). It was later proposed by the same
group (Sobell and group) with some modifications to the initial three-dimensional
structure that actinomycin complexes with a premelted β-DNA conformation that is
present at the transcriptional complex. The complex is not aptly twofold symmetric,
and due to this, the compound binds firmly to a particular guanine molecule thereby
staying more firmly to one chain when compared to the opposite chain. Thus the new
proposed modification clarifies that actinomycin binds to β-DNA in a completely
different structural form but not with B-DNA. The author clarified that β-DNA
behaves as an imperious structural intermediate that is metastable in DNA melting.
This understanding of β-DNA has concreted the action mechanism of actinomycin.
V.M. Dan and R. Sanawar
Arenicolide is a type I polyketide produced by the marine actinomycetes
Salinispora arenicola. The microbe was isolated from marine sediment samples collected from the island of Guam. At an IC 50 touching 30ug/mL the compound arenicolide A showed cytotoxicity toward human colon adenocarcinoma cell line
HCT-116 (Williams et al. 2007). Saliniketal A and B are two other polyketides
sourced from the same strain of actinomycetes. Saliniketal inhibits the expression of
ornithine decarboxylase (ODC). ODC is highly expressed in many cancers and
remains as a major focus for chemoprevention of cancer (Gerner and Meyskens
2004). Chalcomycin is a macrolide with antitumor potential produced by Streptomyces
sp. M491 isolated from samples collected from Qingdao, coastal region of China.
Compounds similar to Chalcomycin were isolated from another Streptomyces strain
B7064 found from mangrove sediments in Hawaii (Asolkar et al. 2002).
7.3
Antitumor Agents and Mechanism of Action
Knowledge of the mechanism undertaken by an agent to kill cancer cells will help in
getting a picture of the possible events that will undergo after the therapy is started. It
will also help in allowing structural modification of the drug, thereby increasing specificity, efficiency, and safety. The mechanism of action employed by the drug will pave
way for understanding the reasons as to why a particular side effect has occurred in
response to a drug. Combinational chemotherapies will be successful when two drugs
can complement each other’s drawbacks, but for a successful combination the actionmechanism of both drugs should be well researched to avoid any adverse effects.
Actinomycin D was the first and oldest microbial metabolite to be approved for
treatment of cancer. Actinomycin A is a close relative of actinomycin D; it was isolated from Streptomyces antibioticus. Actinomycin has a cyclic polypeptide structure
that helps it to selectively bind DNA and block transcription (Reich and Goldberg
1964; Goldberg et al. 1962). This transcription-inhibiting property helps by interfering with the function of RNA polymerase. In particular, transcription at ribosomal
level is found to be most sensitive to the action of actinomycin (Perry 1963). The
initial x-ray crystallography study of actinomycin-deoxyguanosine complex stated a
possible three-dimensional structure of actinomycin binding to DNA. Based on this
study, it was highly believed that the phenoxazone ring present in actinomycin positions into the space between adjacent base pairs and the pentapeptide chain in the
B-helix narrow groove. The formation of hydrogen bonds takes place with guanine
residues in the opposite chain (Sobell et al. 1971). It was later proposed by the same
group (Sobell and group) with some modifications to the initial three-dimensional
structure that actinomycin complexes with a premelted β-DNA conformation that is
present at the transcriptional complex. The complex is not aptly twofold symmetric,
and due to this, the compound binds firmly to a particular guanine molecule thereby
staying more firmly to one chain when compared to the opposite chain. Thus the new
proposed modification clarifies that actinomycin binds to β-DNA in a completely
different structural form but not with B-DNA. The author clarified that β-DNA
behaves as an imperious structural intermediate that is metastable in DNA melting.
This understanding of β-DNA has concreted the action mechanism of actinomycin.
V.M. Dan and R. Sanawar