Diacylglycerol Signaling

410 A. Basu
DNA. Because chemotherapeutic agents often kill actively proliferating cells,
several slow-growing tumors do not respond to these drugs effectively. In addition,
some tumors are inherently resistant to anticancer treatments. Although the majority
of tumors initially respond to chemotherapy, they often become refractory to
subsequent treatments. Both intrinsic and acquired resistance to these chemotherapeutic
drugs poses a significant problem in cancer chemotherapy, and there have
been concerted efforts to understand the bases of chemoresistance. There are two
broad mechanisms of resistance to anticancer drugs: (1) a decreased availability of
drugs to interact with its target DNA, and (2) a failure to recognize and respond to
DNA damage.
Protein kinase C (PKC) is a potential target for cancer therapy because of its
important role in carcinogenesis. It has also been shown to regulate cellular sensitivity
to anticancer agents. In 1984, Joe Bartino and colleagues (Schornagel et al.
1984) demonstrated that PKC inhibitors were active against cells with both intrinsic
and acquired resistance to methotrexate (MTX). The association between PKC and
drug resistance was heralded by the seminal observation of Fine et al. that the
activation of PKC could induce multiple drug resistance (MDR) (Fine et al. 1988).
Since then, there has been a veritable deluge of scientific literature in the late 1980s
and 1990s linking PKC with the multiple drug-resistant phenotype. This excitement,
however, subsided when it was demonstrated that PKC-mediated phosphorylation
of the major drug efflux pump P-glycoprotein that contributes to MDR had
little effect on drug resistance. Alternate mechanisms by which PKC could contribute
to MDR have been explored. Furthermore, an attempt was made to associate a
particular PKC isozyme with a drug-resistant phenotype. The involvement of PKC
was also extended to resistance to other anticancer drugs such as cisplatin that do
not belong to the group of drugs that contribute to MDR.
Although it was originally believed that the inhibition of cell proliferation was the
major cause of anticancer activity of the conventional cytotoxic chemotherapeutic
drugs, it was later realized that these anticancer agents could kill cancer cells by
inducing apoptosis (Fisher 1994). Thus, a failure to undergo apoptosis due to deregulation
in apoptotic signaling pathways could also contribute to chemoresistance.
Several members of the PKC family, including PKCd, -q, -e, and -z have been
shown to be substrates for caspases. While some members of the PKC family are
needed for cell death by apoptosis, others could in fact inhibit cell death and contribute
to chemoresistance. There are two major pathways of cell death by apoptosis: intrinsic
and extrinsic. DNA damaging agents primarily affect the intrinsic or mitochondrial
cell death pathway, and PKC isozymes have been shown to regulate members of the
Bcl-2 family proteins that regulate the mitochondrial cell death pathway. An increase
in antiapoptotic and a decrease in proapoptotic Bcl-2 family members can also
contribute to chemoresistance. The purpose of this book chapter is to assimilate
recent evidence on how the PKC signaling pathway contributes to chemoresistance.
Some earlier studies will be discussed to provide a historical perspective. The focus
of this chapter is in three main areas: (1) MDR, which includes a majority of
conventional chemotherapeutic drugs; (2) resistance to cisplatin, which is highly
effective for the treatment of solid tumors; and (3) a defect in apoptosis, which also
contributes to resistance to multiple chemotherapeutic drugs.