Drawing on the Idea of Induced Differentiation to Explore Precision Chinese-Medicine Treatment of Cancer

Doctor zhou February 4, 2021

Induction-differentiation therapy refers to a treatment method in which, under the action of certain in vivo or in vitro differentiation-inducing agents, malignant tumor cells are induced to evolve and differentiate toward normal cells. Through induced differentiation, the biological characteristics of malignant tumor cells (including markers in gene expression) move closer to those of normal cells, and may even transform completely into normal cells.

The medical community has observed that some tumor patients experience spontaneous tumor regression. For example, the team of Zhang Jinhua from Shengjing Hospital of China Medical University reported that in the 1970s they admitted a male child with a huge abdominal tumor accompanied by ascites, unable to lie flat, and with systemic cachexia. During exploratory laparotomy, the mass was found adherent to the kidney and draped over the abdominal aorta and could not be resected; pathology showed late-stage neuroblastoma with multiple lymph-node metastases. The child was sent home immediately without any treatment. Two years later the child returned for follow-up in good condition, moving freely, with a soft, flat abdomen; B-ultrasound found no mass and no enlarged lymph nodes. The child had self-healed with no treatment at all. Similar spontaneous-healing cases have been reported by Beijing Children's Hospital, and from time to time cancer patients around the world experience spontaneous tumor regression.

Why do these tumor patients self-heal? Part of the reason may be spontaneous differentiation and reversal of the tumor under the influence of endogenous differentiation-inducing agents. This phenomenon has attracted academic attention; in recent years scholars around the world have carried out a great many clinical trials exploring induced differentiation and have achieved many results.

In 1995, Zhang Peng et al. of Harbin Medical University reported their team's clinical and experimental research, begun in 1992, on treating acute promyelocytic leukemia (APL) with arsenic trioxide (As2O3). They found that As2O3 not only induces differentiation and suppresses clones in APL but also promotes apoptosis of leukemia cells. Zhang Peng's team observed the morphological features of apoptosis in APL cells.

In 2017, the team of Zhang Jinhua at Shengjing Hospital of China Medical University published the book Induction-Differentiation Therapy of Neuroblastoma, reporting that over the past decades their team used low-dose chemotherapy to induce differentiation of neuroblastoma (NB), treating 199 NB patients (166 of them stage IV). Results: CR in 71 cases, PR in 45, SD in 25, PD in 4, 49 deaths, and 5 lost to follow-up.

The greatest difference between normal cells and tumor cells is that normal cells possess a complete set of apoptotic mechanisms. Under various influences, after growing to a certain extent, cells automatically undergo apoptosis. So when cells grow excessively, or when the body needs growth and development, normal cells can maintain overall stability through automatic apoptosis; but tumor cells do not undergo automatic apoptosis.

The failure of tumor cells to undergo automatic apoptosis may be related to telomerase. At the ends of eukaryotic chromosomes there is a special structure called the telomere; the telomere regulates the normal death of cells through the shortening of its own length. With the help of telomerase, tumor cells can continuously encode telomeric DNA repeats to replenish the telomeres, breaking the cell's own balance and allowing tumor cells to grow indefinitely.

So if tumor cells can be induced to differentiate into normal cells, the process of indefinite tumor-cell growth can be terminated, achieving the goal of spontaneous tumor regression. To do this, we must change the body's internal and external environment as much as possible and give full play to the differentiation-inducing action of various treatment methods.

From a molecular-biology perspective, for tumor cells to undergo apoptosis they need the help of tumor suppressor genes (such as the wild-type P53 gene). A great deal of research shows that many anticancer drugs kill tumor cells by activating tumor suppressor genes and starting the apoptotic mechanism.

Chinese medicine has a long history of treating cancer and offers much valuable experience to draw on. The arsenic trioxide used by Zhang Peng's team mentioned above to treat acute promyelocytic leukemia was itself drawn from cases in which folk Chinese medicine used arsenic (pishuang, whose main component is arsenic trioxide) to treat cancer. Traditional Chinese medicine summarizes the antitumor action of arsenic compounds such as arsenic and realgar (xionghuang) as "using poison to attack poison"; modern scientists have explained through experiments that its main antitumor mechanism is inducing apoptosis.

Over the years I have witnessed many cases in which tumors spontaneously regressed after traditional Chinese therapy, and the mechanism behind this is worth exploring. Some patients' tumors regressed after they inhaled the smoke of herbs such as arsenic; some regressed after they took certain oral Chinese medicines; and some even achieved spontaneous tumor regression relying solely on the simple therapy of moxibustion.

But the experience of most such patients is not reproducible; when other patients follow their example, the treatment is usually ineffective. To raise the success rate, in recent years I have been exploring the idea of using broad-spectrum, multi-target anticancer Chinese herbal formulas; for details see my article 《我用中药复方多靶点广谱抗癌的实践经验介绍》. This approach has a degree of reproducibility and has achieved certain results in several patients with various tumors, with a few patients reaching CR.

But this protocol's effective rate still does not reach my ideal, so over these years I have continued to refine this approach. Based on feedback from a large number of patients after treatment, I adjust the herbal formula every half month. In this process of constant exploration and improvement, the protocol's effective rate is gradually rising. But I have also noticed a problem: some patients for whom this protocol was completely ineffective achieved some effect after using other protocols.

For example, Zhao, an ovarian cancer patient in Gansu, is a fellow patient of Chen, a stage 4C ovarian cancer patient I treated (Chen has now achieved CR; for the case report see my article 《历时近三年，用中药把一个4C期卵巢癌患者的转移瘤全消除》). Zhao was referred by Chen. The protocol that worked for Chen was not only ineffective in Zhao but actually caused Zhao's tumor marker CA125 to rise rapidly. But after I adjusted the medication, abandoned anticancer treatment for Zhao, and used only Chinese medicine's support-the-righteous-qi therapy, the rate at which Zhao's CA125 rose slowed markedly.

Cases like this show that for different patients, the same treatment protocol may sometimes be used, while at other times a different protocol must be used to achieve the desired induction-differentiation effect. For instance, when I applied Chen's protocol to Ma, a patient with advanced cervical cancer, Ma also achieved CR; for Ma's case report see my article 《晚期宫颈癌患者马某治疗医案（肿瘤已全部消除）》.

I have also applied Chen's protocol to several children with neuroblastoma; after taking the medicine, all showed the phenomenon of spontaneous tumor regression. But when I applied that protocol to Zhao, who had the same cancer as Chen, the result was unsatisfactory. And after giving Zhao purely support-the-righteous-qi therapy, the rate of tumor-cell proliferation in Zhao again slowed. This shows that when fighting cancer with Chinese medicine, one cannot rely entirely on a single approach. We need to explore further before we can find more precise treatments.

Traditional Chinese medicine has long held that the same disease may be treated differently and different diseases may be treated the same way—meaning that the same illness sometimes requires different methods, while different illnesses may sometimes respond to the same method. It is just that from ancient times to the present, no approach with a particularly high effective rate has taken shape in treating tumor-type diseases. So we, as a new generation of Chinese medicine practitioners, need to integrate new knowledge, continually practice and explore, and raise the effective rate of Chinese medicine in diagnosing and treating cancer.

The essence of the induction-differentiation approach is to rely on in vivo and in vitro differentiation-inducing agents to induce tumor cells to transform into normal cells. This requires working from three angles: first, improving the patient's internal environment; second, boosting the patient's own immunity; third, inducing tumor cells to undergo automatic apoptosis.

Improving the patient's internal environment can slow the rate of tumor-cell proliferation. The root cause of a malignant tumor growing in the body is an imbalance caused by excessive tumor-cell proliferation and insufficient apoptosis; if tumor-cell proliferation slows and apoptosis speeds up, the tumor has a hope of spontaneously regressing.

The body produces tumor cells under the stimulation of carcinogenic factors. But carcinogenic factors cannot act alone; the body's internal environment plays a large role in whether carcinogenic factors cause genetic mutation in the body. The internal environment of most cancer patients is poor, and this environment creates the conditions for tumor-cell proliferation. If we can correct the deviation in the body's internal environment, the rate of tumor-cell proliferation will fall, the rate of tumor growth will slow, and the patient's survival time can be extended.

According to the biological theory of homeostasis, an organism can control its own internal environment and keep it relatively stable. This homeostasis reduces the organism's dependence on external conditions and raises its tolerance of ecological factors. If an organism's homeostasis is not disrupted, it can resist the stimulating effects of external ecological factors (such as certain carcinogens and carcinogenic environments) and avoid malignant transformation under their influence. But once an organism's homeostasis is disrupted, its tolerance of external ecological factors drops greatly, and canceration readily occurs.

We can find similar statements in traditional Chinese medical theory. Traditional Chinese medicine holds that when yin is calm and yang is tightly bound, the spirit is in harmony; only when the body's yin and yang are balanced and in a stable state can it stay healthy. If yin and yang fall out of balance, the body's internal stability is disrupted, and health problems readily arise. That is why Chinese medicine stresses that in treating illness one must seek the root, and the root lies in yin and yang; the foundation of Chinese medical treatment is bringing the body into a state of yin-yang balance.

Of course, we must not be bound by the original concepts of yin and yang, but we can draw on this Chinese medical way of thinking for treating illness. If we correct the deviations in the patient's internal environment and restore the patient's homeostasis—what Chinese medicine calls bringing the patient into a state of yin-yang balance—then the rate at which the patient's tumor grows will slow markedly.

For example, a tumor patient whom Chinese medicine sees as having a heat-toxin-exuberant constitution has clearly already disrupted his homeostasis. When Chinese medicine uses the approach of clearing heat and detoxifying to resolve the heat-toxin exuberance and improve the patient's yin-yang imbalance, the rate of tumor growth slows considerably. And the heat-toxin exuberance of Chinese medicine is, in many cases, exactly what Western medicine calls an inflammatory state; we know that improving the inflammatory state of cancer patients can slow the rate at which their tumors develop.

Or take a tumor patient whom Chinese medicine sees as having a blood-stasis constitution. Such patients generally are especially prone to forming new blood vessels within the tumor; to adjust this imbalance, Chinese medicine must use herbs that activate blood and resolve stasis. In fact, most Chinese herbs that activate blood and resolve stasis and soften and dissipate hard lumps have a good inhibitory effect on angiogenesis. The reason the patent medicine Xihuang Pills has anticancer effects is related to its inhibition of angiogenesis. Many Western anticancer drugs, such as bevacizumab and anlotinib, also exert their therapeutic effect through anti-angiogenesis.

Seen this way, many ideas of Chinese medicine are consistent with those of Western medicine and modern biology. We can draw on this new knowledge to clarify the therapeutic principles of ancient Chinese medicine and explore Chinese anticancer approaches more precisely.

The patient's own immunity also has a great deal to do with the development and progression of cancer. As everyone knows, when immunity is low, tumor cells develop rapidly. For this reason, compared with traditional radiotherapy and chemotherapy, many modern oncologists prefer new concepts such as metronomic chemotherapy. Metronomic chemotherapy means giving small doses of chemotherapy drugs (usually 1/10 to 1/3 of the conventional dose) relatively frequently; in substance it is still the anti-angiogenesis mentioned above. The Zhang Jinhua team at Shengjing Hospital of China Medical University mentioned above is a representative in this regard; for years they have been treating children with neuroblastoma with low-dose chemotherapy plus Chinese medicine, achieving good outcomes.

Compared with traditional high-dose chemotherapy, metronomic chemotherapy has a major advantage: it damages the patient's body relatively little, so the patient's immunity is not destroyed too severely. Many children with neuroblastoma who go to countries such as Spain for treatment and then return to China find they cannot adapt to the high-dose traditional chemotherapy used domestically. Because the low-dose chemotherapy they received abroad did not affect their quality of life and required no hospitalization, while the high-dose chemotherapy they received after returning home clearly impaired their quality of life and required long hospitalization, causing inconvenience and a very poor experience.

Chinese medicine's support-the-righteous-qi therapy mainly controls the development of tumor cells by raising the patient's immunity. In the present era where Chinese and Western medicine coexist, Chinese medicine's support therapy also has the use of reducing the side effects of Western radiotherapy and chemotherapy. For instance, many cancer patients undergoing radiotherapy, chemotherapy, or oral targeted therapy experience sharp drops in white cells, red cells, and platelets, with low immunity; when these patients also receive Chinese medicine, the above problems can be properly resolved, and the effects of radiotherapy, chemotherapy, and targeted therapy can be improved. Such immunity-boosting treatment has real practical value for cancer patients.

Likewise, on the question of inducing tumor-cell apoptosis, Chinese medicine can also play a role. For instance, the arsenic compounds used in traditional Chinese medicine mentioned above—arsenic (arsenic trioxide) and realgar—have the effect of inducing tumor-cell apoptosis. Besides arsenic, many of the poison-attacking-poison drugs used in Chinese medicine also induce tumor-cell apoptosis.

So we can absolutely work from the three angles above to explore approaches to precision Chinese-medicine treatment of cancer. But at the same time we must study the toxicity of traditional Chinese herbs; over the years I have also seen many patients whose liver and kidney function were damaged after taking anticancer Chinese medicine. Among the patients I myself treat, there have also been those with damaged liver and kidney function. The ideal medical protocol is both safe and effective; while pursuing effectiveness, we must also raise safety as much as possible.

I very much look forward to Chinese and Western medicine cooperating on induction-differentiation therapy for tumor patients and jointly exploring new treatment protocols for cancer patients. I am also glad to introduce this concept to cancer patients and their families, believing it can help patients and their families make more rational choices.

You should also read: