Vitamin D and Other Differentiation-promoting Agents as Neoadjuvants for Photodynamic Therapy of Cancer

Abstract

The efficacy of photodynamic therapy (PDT) using aminolevulinic acid (ALA), which is preferentially taken up by cancerous cells and converted to protoporphyrin IX (PpIX), can be substantially improved by pretreating the tumor cells with vitamin D (Vit D). Vit D is one of several "differentiation-promoting agents" that can promote the preferential accumulation of PpIX within the mitochondria of neoplastic cells, making them better targets for PDT. This article provides a historical overview of how the concept of using combination agents ("neoadjuvants") for PDT evolved, from initial discoveries about neoadjuvant effects of methotrexate and fluorouracil to later studies to determine how vitamin D and other agents actually work to augment PDT efficacy. While this review focuses mainly on skin cancer, it includes a discussion about how these concepts may be applied more broadly toward improving PDT outcomes in other types of cancer.

Fig. 1.

The heme synthetic pathway. Heme is a 4-ring porphyrin molecule that is a used as a cofactor in many kinds of enzymes, including hemoglobin. Its synthesis requires 8 enzymatic conversion steps (numbered 1–8). The necessary enzymes are ALAS, aminolevulinic acid synthase; ALAD, aminolevulinic acid dehydratase; PBGD, porphobilinogen deaminase; UCS, uroporphyrinogen III cosynthase; UDC, uroporphyrinogen decarboxylase; CPO, coproporphyrinogen oxidase; PPO, protoporphyrinogen oxidase; FC, ferrochelatase. In the final reaction step, catalyzed by ferrochelatase, an atom of iron is inserted into the protoporphyrin IX (PpIX) molecule. The system is normally shut off by negative feedback inhibition at the first step, but this can be bypassed by adding large amounts of exogenous 5-ALA, which leads to accumulation of high levels of PpIX. Adapted from ref. (34).

Fig. 2.

Analysis of the expression of mitochondrial enzymes most commonly involved in regulation of heme synthesis. Subcutaneous tumors (A431 squamous cell carcinoma line) in mice pretreated with calcitriol (Vit D) or with vehicle alone, were analyzed by Western blotting (A). Densitometric quantification of 3 tumors per condition is shown (B). ALAD, aminolevulinic acid dehydratase; PBGD, porphobilinogen deaminase; CPO, coproporphyrinogen oxidase; FC, ferrochelatase. GAPDH, glyceraldehyde 3-phosphate dehydrogenase (loading control). Reproduced with permission from ref (37).

Fig. 3.

Effect of Vit D combination pretreatment upon the transcription of the CPO gene. Vit D may act indirectly by increasing the expression of C/EBP transcription factors; these C/EBP factors bind to the upstream CPO gene promoter region and cooperate with other factors to stimulate gene transcription. Adapted from ref. (41).

Fig. 4.

Vitamin D is both an oral vitamin and a steroid-like hormone. Adapted from ref. (51).