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Despite remarkable progress in the discovery and development of novel cancer therapeutics, cancer remains the second leading cause of death in the world. For many years, compounds derived from plants have been at the forefront as an important source of anticancer therapies and have played a vital role in the prevention and treatment of cancer because of their availability, and relatively low toxicity when compared with chemotherapy. More than 3000 plant species have been reported to treat cancer and about thirty plant-derived compounds have been isolated so far and have been tested in cancer clinical trials. The mechanisms of action of plant-derived anticancer drugs are numerous and most of them induce apoptotic cell death that may be intrinsic or extrinsic, and caspase and/or p53-dependent or independent mechanisms. Alternative modes of cell death by plant-derived anticancer drugs are emerging and include mainly autophagy, necrosis-like programmed cell death, mitotic catastrophe, and senescence leading to cell death. Considering that the non-apoptotic cell death mechanisms of plant-derived anticancer drugs are less reviewed than the apoptotic ones, this paper attempts to focus on such alternative cell death pathways for some representative anticancer plant natural compounds in clinical development. In particular, emphasis will be on some promising polyphenolics such as resveratrol, curcumin, and genistein; alkaloids namely berberine, noscapine, and colchicine; terpenoids such as parthenolide, triptolide, and betulinic acid; and the organosulfur compound sulforaphane. The understanding of non-apoptotic cell death mechanisms induced by these drugs would provide insights into the possibility of exploiting novel molecular pathways and targets of plant-derived compounds for future cancer therapeutics.

Thymoquinone (TQ), a component of black seed essential oil, is known to induce apoptotic cell death and oxidative stress, however, the direct involvement of oxidants in TQ-induced cell death has not been established yet. Here, we show that TQ inhibited the proliferation of a panel of human colon cancer cells (Caco-2, HCT-116, LoVo, DLD-1 and HT-29), without exhibiting cytotoxicity to normal human intestinal FHs74Int cells. Further investigation in DLD-1 revealed that apoptotic cell death is the mechanism for TQ-induced growth inhibition as confirmed by flow cytometry, M30 cytodeath and caspase-3/7 activation. Apoptosis was induced via the generation of reactive oxygen species (ROS) as evidenced by the abrogation of TQ apoptotic effect in cells preincubated with the strong antioxidant N-acetyl cysteine (NAC). TQ increased the phosphorylation states of the mitogen-activated protein kinases (MAPK) JNK and ERK, but not of p38. Their activation was completely abolished in the presence of NAC. Using PD98059 and SP600125, specific ERK and JNK inhibitors, the two kinases were found to possess pro-survival activities in TQ-induced cell death. These data present evidence linking the pro-oxidant effects of TQ with its apoptotic effects in colon cancer and prove a protective role of MAPK.

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