Expert Review Programmed Cell Death Pathways and Current Antitumor Targets Mei Lan Tan, 1,2,4 Jer Ping Ooi, 1 Nawfal Ismail, 1 Ahmed Ismail Hassan Moad, 1 and Tengku Sifzizul Tengku Muhammad 2,3 Received February 12, 2009; accepted April 11, 2009; published online April 30, 2009 Abstract. Apoptosis and autophagic cell deaths are programmed cell deaths and they play essential roles in cell survival, growth and development and tumorigenesis. The huge increase of publications in both apoptosis and autophagic signaling pathways has contributed to the wealth of knowledge in facilitating the understanding of cancer pathogenesis. Deciphering the molecular pathways and molecules involved in these pathways has helped scientists devise and develop targeted strategies against cancer. Various drugs targeting the apoptotic TRAIL, Bcl-2 and proteasome pathways are already in Phase II/III clinical trials. The first mTOR inhibitor, temsirolimus has already been approved by the FDA, USA for the treatment of advanced renal cell carcinoma and more mTOR inhibitors are expected to be in the market in a few years time. Strategizing against aberrant autophagy activities in various cancers by using either pro-autophagics or autophagy inhibitors are currently been investigated. This review aims to discuss the most recent antitumor strategies targeting the apoptosis and autophagy signaling pathways and the latest outcome of clinical trials of the above drugs. KEY WORDS: apoptosis; autophagy; autophagic cell death; cancer; programmed cell death. INTRODUCTION Cell death plays an important role in the development and homeostasis of normal tissues (1,2) and has profound effects on cancer growth and progression (3–5). An imbalance between cell proliferation and cell death is known to link to human diseases including cancer, autoimmune disease, neu- rodegenerative disorders, viral infections and AIDS (6–10). Current cancer therapies are based on the removal of solid tumor masses and are usually followed by a series of chemical or physical treatments such as chemotherapy and radiother- apy. The ability of these therapies to induce death of these rapidly growing cells forms the very basis of cancer therapy. Most chemotherapeutic agents as well as ionizing radiation utilize the endogenous mechanisms to induce programmed cell deaths (11,12). Further deciphering of the mechanisms and signaling pathways of these cell deaths have brought forward a new paradigm in which cancer may be efficiently targeted. Novel and specific cancer therapeutics and techni- ques directed at members of the cell deaths signaling path- ways are being developed and currently being tested in clinical trials. The two major types of cell deaths, namely apoptosis and autophagic cell death, the most recent anti- tumor strategies targeting these cell death pathways and some of the novel anticancer drugs will be discussed. APOPTOSIS, CANCER AND THERAPEUTIC TARGETS Historically, the term programmed cell death (PCD) was first mentioned by Lockshin and Williams in 1965 (13). The phenomenon was used to describe the coordinated deaths of certain larval muscles during transformation into adult moths. Kerr and co-workers later described a series of similar morphological characteristics which accompanied the deaths of a variety of tissue sources, which was then coined as “apoptosis” (14). The phenomenon of apoptosis was in fact discovered earlier by Carl Vogt in 1842 (15). However, it was decades later before the term apoptosis was adopted and generated a continuous interest in this field of science. Apoptosis or Type 1 cell death is a distinct mode of cell death that is fundamentally different from other forms of cell death based on its morphology, biochemistry and incidence (12). Apoptosis and mitosis share some commonality and are thought to be equal and opposite in a kinetic sense, envisaged as a push–pull relationship, which in normal conditions, exists in dynamically equilibrium state (16). Apoptotic processes are known to have widespread biological significance as they play important roles in cell development, proliferation/homeostasis, differentiation, regulation of the immune system and in the removal of defect and harmful cells. The earliest recognized morphological changes in apo- ptosis involve compaction and segregation of nuclear chro- matin and condensation of the cytoplasm (12,14). The plasma membrane convolutes or blebs in a florid manner, producing 1547 0724-8741/09/0700-1547/0 # 2009 Springer Science + Business Media, LLC Pharmaceutical Research, Vol. 26, No. 7, July 2009 ( # 2009) DOI: 10.1007/s11095-009-9895-1 1 Advanced Medical and Dental Institute, Universiti Sains Malaysia, Lot 1–8, Persiaran Seksyen 4/1, Bandar Putra Bertam, Kepala Batas, Pulau Pinang, Malaysia. 2 Malaysian Institute of Pharmaceuticals and Nutraceuticals, Ministry of Science and Technology and Innovation, Pulau Pinang, Malaysia. 3 Faculty of Science and Technology, Universiti Malaysia Terengganu, Kuala Terengganu, Terengganu, Malaysia. 4 To whom correspondence should be addressed. (e-mail: tanml@usm. my, tanml@amdi.usm.edu.my)