**8. Conclusions and future prospects**

As described previously, the promoter regions of a number of genes that encode TCA cycle enzymes and DNA repair factors contain duplicated GGAA (TTCC) motifs [53, 54]. Thus, the fine-tuning of the transcription of mitochondrial function-associated factor- and DNA repair factor-encoding genes would be required for cells to conduct mitochondria in response to

In cancer cells, the mitochondrial functions are downregulated but glycolysis is upregulated [7, 8]. Thus, inhibitors of glycolysis/PDHK1/PARP, which target the metabolic switch in cancer cells, could be effective anti-cancer drugs [59]. In general, glycolysis- or glycolytic pathwaytargeting drugs are expected to kill cancer cells specifically. For example, 2-deoxy-d-glucose, cisplatin and 5-FU—which have an inhibitory effect on glycolysis—are used to treat cancer in the clinical setting [177]. However, glycolysis is one of the most essential biological reactions. Thus, glycolysis inhibitors may be harmful or toxic to normal cells. Given that mitochondrial dysfunction is another essential cause of oncogenesis, the improvement of the mitochondria might provide clues that can be used to design innovative next-generation cancer therapies.

Our previous *in vitro* studies showed that Rsv moderately upregulates the expression of various duplicated GGAA-motif-driven genes, including *TP53* and *HELB* [46, 48, 78]. Given that

tion of the redox reaction-associated genes may be applied in cancer treatment. PARP inhibitors, which are especially effective for treating cancer with BRCA1 and BRCA2 mutations by disrupting specific types of DNA repair systems, are clinically approved drugs [89]. Another compound is TEMPOL, an antioxidant that has a suppressive effect on tumor cell prolif-

[179, 180]. A number of compounds that target mitochondria have been tested in clinical trials [181]. Tocotrienols and their analogues target mitochondria and the immune system, causing the death of cancer cells [182]. Metformin and rapamycin are also expected to be novel anti-cancer/aging drugs that effectively suppress mTOR signaling [183]. Activators of mTOR, AMPK, and PGC-1α have been shown to have a synergistic effect with PD-1 blockade therapy

PGC-1α, which is encoded by the *PPARGC1A* gene, has been shown to be involved in the *de* 

tifunctional protein, which suppresses tumors through its effects on the mitochondrial lipid metabolism [185]. LACTB is included in mitochondrial complex I and treatment of fibroblast cells with its siRNA reduces complex I activity [186]. It therefore works as an upregulator

[184], suggesting that mitochondrial activation can augment the immune response.

**7.2. Possible gene-therapies that improve the mitochondrial functions**

/NADH ratio can improve the mitochondrial functions, the introduc-

[172]. Recently, it was reported that lactamase β (LACTB) is a mul-

level, supporting the DNA repair system

**7. The development of novel cancer therapeutics to improve** 

**7.1. Chemicals that will initiate the recovery of mitochondria**

eration [178], which increases the cellular NAD+

DNA damage-inducing stress.

118 Mitochondrial Diseases

**mitochondrial functions**

the increase in the NAD+

*novo* synthesis of the NAD+

In this article, we focused on the transcription mechanism that regulates the mitochondrial functions and the DNA repair systems, both of which decline with aging. Although the molecular mechanisms underlying the regulation of the expression of these genes are not yet fully understood, several lines of evidence suggest that it is dependent on the NAD+ /NADH balance.

The anti-cancer drugs that are currently in use, including metabolism inhibitors, telomerase inhibitors, and apoptosis inducers, were developed with the common intention of killing cancer cells. Although immune receptor target drugs have been applied in the clinical setting, they are similar in that they force cancer cells to die. The anti-cancer drugs that are currently in use damage both malignant cancer cells and normal healthy cells. Importantly, the undesired effects of these anti-cancer drugs are problematic with regard to the quality of life (QOL) of cancer patients, especially those who are too old to endure severe adverse effects that occur during the course of chemotherapy. In order to avoid lethal side effects, individual whole genome sequencing to identify drug sensitivities, the development of a side-effect monitoring system, and the improvement of treatment policies could be adapted. These are the burdens that are necessitated by the intrinsic concept underlying the development and creation of most anti-cancer drugs.

**Author details**

Fumiaki Uchiumi1

Science, Noda, Chiba-ken, Japan

Science, Noda, Chiba-ken, Japan

Sei-ichi Tanuma2

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A New Insight into the Development of Novel Anti-Cancer Drugs that Improve the Expression…

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http://dx.doi.org/10.5772/intechopen.71095

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In the near future, novel anti-cancer drugs or therapies must be developed and established. These drugs should not kill cancer cells; rather they should give them a chance to regain the right mitochondrial functions and DNA repair systems, and immunological responses. Natural or chemical compounds can ameliorate the NAD+ /NADH level to improve the mitochondrial functions, DNA repair systems, and even immune responses. Alternatively, specific TF expression vector(s) could be introduced into cancer cells to lead them to recover to a healthy state. A number of promoter regions of the mitochondrial function-, DNA repair-, and anti-viral/tumor factor-encoding genes have duplicated GGAA-motifs with GC-boxes. Needless to say, it is necessary to determine the TFs that should and should not be applied prior to their clinical use. Based on this novel concept, the design of anticancer/tumor drugs or gene transfer vector(s) will contribute to the prevention of aging and its associated diseases, including cancer.
