Starvation, detoxification, and multidrug resistance in cancer therapy

Abstract

The selection of chemotherapy drugs is based on the cytotoxicity to specific tumor cell types and the relatively low toxicity to normal cells and tissues. However, the toxicity to normal cells poses a major clinical challenge, particularly when malignant cells have acquired resistance to chemotherapy. This drug resistance of cancer cells results from multiple factors including individual variation, genetic heterogeneity within a tumor, and cellular evolution. Much progress in the understanding of tumor cell resistance has been made in the past 35 years, owing to milestone discoveries such as the identification and characterization of ABC transporters. Nonetheless, the complexity of the genetic and epigenetic rewiring of cancer cells makes drug resistance an equally complex phenomenon that is difficult to overcome. In this review, we discuss how the remarkable changes in the levels of glucose, IGF-I, IGFBP-1 and in other proteins caused by fasting have the potential to improve the efficacy of chemotherapy against tumors by protecting normal cells and tissues and possibly by diminishing multidrug resistance in malignant cells.

Fig. 1

The conserved role of IGF-I in lifespan regulation and stress resistance. The insulin/IGF-I signaling pathway plays a major role in regulating lifespan and cellular stress resistance. Deficiencies in these pathways have been shown to convey protection to the cell/organism against multiple toxins.

Fig. 2

Fasting and DR modulate drug metabolism. Fasting and DR have been shown to affect all 3 major phases of drug metabolism. Phase I involves redox and hydrolysis and is mediated by the cytochrome P450 family. Phase II are usually detoxification processes that involves conjugation steps. Genes under this category are regulated by the stress responsive master transcription factor Nrf2. Proteins classified as phase III are involved in transport, such as members of the ABC superfamily of transporters.

Fig. 3

A model for DSR in response to fasting. In a variety of normal cells, downstream elements of the IGF-I and other growth factors pathways, including the Akt, Ras and other proto-oncogenes, can be down-regulated in response to the reduction in growth factors caused by starvation. This down-regulation can block/reduce growth and promotes protection. By contrast, oncogenic mutations render tumor cells less responsive to fasting due to their constitutive pro-growth mode and relative independence from anti-growth signals. Constitutive activation of one of the pro-growth pathways may be sufficient for the continued growth. Therefore, cancer cells fail to or only partially respond to starvation conditions and continue to promote growth instead of entering a protected mode.

Fig. 4

Fasting selectively protects normal cells from chemotherapy toxicity. (A–C) Mice from 3 different genetic backgrounds were fasted for 48–60 h prior to high-dose etoposide administration. (A) A/J mice were fasted for 48 h. (B) CD-1 mice were fasted for 60 h prior to chemotherapy administration. (C) Athymic Nude mice were fasted for 48 h. (D–F) Transgenic mice with a conditional liver igf1 gene deletion (LID) were treated with (D) 2 cycles of high-dose doxorubicin (DXR), (E) high-dose cyclophosphamide (CP), and (F) high-dose 5-FU. (G) LID mice bearing metastatic melanoma were treated with 2 cycles of high-dose DXR. (H) Patients self-reported side-effects after chemotherapy with or without fasting based on the common toxicity criteria (CTC) outlined by the National Cancer Institute (NCI).